TY  - CONF
AU  - Guševac Stojanović, Ivana
AU  - Dragić, Milorad
AU  - Zarić Kontić, Marina
AU  - Martinović, Jelena
AU  - Mitrović, Nataša
AU  - Stojanović, Zoran
AU  - Veljković, Filip
AU  - Martinović, D.
AU  - Grković, Ivana
AU  - Drakulić, Dunja
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11058
AB  - Cerebral hypoperfusion (CH) is recognised as a contributor to various impairments characteristic for elderly population and patients with vascular dementia and Alzheimer’s disease. CH-induced brain damage is linked with oxidative stress in the cells that can cause DNA fragmentation and cell death, reflected through a change in cells’ morphology. Our study investigated the beneficial effects of progesterone (P4), a hormone with neuroprotective properties, against CH-induced oxidative stress and neurodegenerative pathologies in rat prefrontal cortex (PFC). For the purpose of the experiment, adult male Wistar rats were dived into groups: (I) animals subjected to permanent bilateral occlusion of common carotid arteries (2VO) treated with vehicle (commercial flax oil, 1 mg/kg/day), (II) animals subjected to 2VO treated with P4 dissolved in vehicle (1.7 mg/kg/day) and (III) animals subjected to sham operation treated with vehicle. Animals were sacrificed after 7 subcutaneous treatments. Levels of pro-/antioxidant balance (PAB) and DNA fragmentation along with cell morphology were estimated by well-defined methods. The results revealed that P4 administration moderated CH-induced impairments in PFC, not only by decreasing PAB level and diminishing DNA fragmentation, but also preserving the cell morphology reflected through clearly defined cell bodies, with round nuclei, prominent nucleolus and visible Nissl bodies in layer III. Obtained results point out that P4 is able to attenuate CH-induced pro-oxidant state and subsequent changes in PFC. This hormone holds promise as an effective agent for the CH treatment, still, its specific actions remain to be discovered.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Progesterone treatment preserves cortical pro-/antioxidant balance, DNA integrity and cell morphology in rat cerebral hypoperfusion model
SP  - 117
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11058
ER  - 

@conference{
author = "Guševac Stojanović, Ivana and Dragić, Milorad and Zarić Kontić, Marina and Martinović, Jelena and Mitrović, Nataša and Stojanović, Zoran and Veljković, Filip and Martinović, D. and Grković, Ivana and Drakulić, Dunja",
year = "2023",
abstract = "Cerebral hypoperfusion (CH) is recognised as a contributor to various impairments characteristic for elderly population and patients with vascular dementia and Alzheimer’s disease. CH-induced brain damage is linked with oxidative stress in the cells that can cause DNA fragmentation and cell death, reflected through a change in cells’ morphology. Our study investigated the beneficial effects of progesterone (P4), a hormone with neuroprotective properties, against CH-induced oxidative stress and neurodegenerative pathologies in rat prefrontal cortex (PFC). For the purpose of the experiment, adult male Wistar rats were dived into groups: (I) animals subjected to permanent bilateral occlusion of common carotid arteries (2VO) treated with vehicle (commercial flax oil, 1 mg/kg/day), (II) animals subjected to 2VO treated with P4 dissolved in vehicle (1.7 mg/kg/day) and (III) animals subjected to sham operation treated with vehicle. Animals were sacrificed after 7 subcutaneous treatments. Levels of pro-/antioxidant balance (PAB) and DNA fragmentation along with cell morphology were estimated by well-defined methods. The results revealed that P4 administration moderated CH-induced impairments in PFC, not only by decreasing PAB level and diminishing DNA fragmentation, but also preserving the cell morphology reflected through clearly defined cell bodies, with round nuclei, prominent nucleolus and visible Nissl bodies in layer III. Obtained results point out that P4 is able to attenuate CH-induced pro-oxidant state and subsequent changes in PFC. This hormone holds promise as an effective agent for the CH treatment, still, its specific actions remain to be discovered.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Progesterone treatment preserves cortical pro-/antioxidant balance, DNA integrity and cell morphology in rat cerebral hypoperfusion model",
pages = "117",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11058"
}

Guševac Stojanović, I., Dragić, M., Zarić Kontić, M., Martinović, J., Mitrović, N., Stojanović, Z., Veljković, F., Martinović, D., Grković, I.,& Drakulić, D.. (2023). Progesterone treatment preserves cortical pro-/antioxidant balance, DNA integrity and cell morphology in rat cerebral hypoperfusion model. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 117.
https://hdl.handle.net/21.15107/rcub_vinar_11058

Guševac Stojanović I, Dragić M, Zarić Kontić M, Martinović J, Mitrović N, Stojanović Z, Veljković F, Martinović D, Grković I, Drakulić D. Progesterone treatment preserves cortical pro-/antioxidant balance, DNA integrity and cell morphology in rat cerebral hypoperfusion model. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:117.
https://hdl.handle.net/21.15107/rcub_vinar_11058 .

Guševac Stojanović, Ivana, Dragić, Milorad, Zarić Kontić, Marina, Martinović, Jelena, Mitrović, Nataša, Stojanović, Zoran, Veljković, Filip, Martinović, D., Grković, Ivana, Drakulić, Dunja, "Progesterone treatment preserves cortical pro-/antioxidant balance, DNA integrity and cell morphology in rat cerebral hypoperfusion model" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):117,
https://hdl.handle.net/21.15107/rcub_vinar_11058 .

TY  - CONF
AU  - Grković, Ivana
AU  - Dragić, Milorad
AU  - Mitrović, Nataša
AU  - Zarić Kontić, Marina
AU  - Martinović, Jelena
AU  - Guševac Stojanović, Ivana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11061
AB  - Adenosine 5'-triphosphate (ATP) and adenosine are versatile signaling molecules involved in many pathophysiological processes in the nervous system. They can be released from all types of brain cells in the extracellular space and activates purinergic receptors. Signaling via extracellular ATP is regulated by cell-surface located ectonucleotidases. Extracellular AMP resulting from the hydrolysis of ATP and ADP can in turn be hydrolyzed into adenosine by ecto-5'-nucleotidase (eN). We examined the involvement of purinergic signaling components in the rat model of trimethyltin (TMT)-induced hippocampal neurodegeneration (8mg/kg, single ip), which results in behavioral and neurological dysfunction similar as in Alzheimer's disease models. Enzyme histochemistry and immunohistochemistry (ir) showed that products of AMPase activity and eN-ir were accumulated in the neuronal strata, infiltrating within neuronal cell layers, depicting individual round-shaped elements that covered neuronal layers with pronounced cell death mostly at the late stage of TMT-induced neurodegeneration. Co-localization with Iba1+ specifically marked eN at amoeboid microglial cells. Neither of the tested pro-inflammatory cytokines (IL-1β, TNF-α, IL10) and C3 nor polarization marker iNOS was found in association with those Iba1/eN+ -cells. Iba1-ir cells co-localized with Arg1-ir and phagocytic marker CD68- ir. Marked induction of P2Y12R-, P2Y6R-, and P2X4-mRNA at the early stage of TMT-induced neurodegeneration might reflect the migration, and chemotaxis of microglia, while induction of P2X7R at amoeboid cells probably modulates their phagocytic role. These findings may contribute to a better understanding of the involvement of purinergic signaling components in the progression of neurodegenerative disorders that could be target molecules for development of novel therapies.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Ecto-5'-nucleotidase marks amoeboid microglial cells in the rat model of neurodegeneration
SP  - 120
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11061
ER  - 

@conference{
author = "Grković, Ivana and Dragić, Milorad and Mitrović, Nataša and Zarić Kontić, Marina and Martinović, Jelena and Guševac Stojanović, Ivana",
year = "2023",
abstract = "Adenosine 5'-triphosphate (ATP) and adenosine are versatile signaling molecules involved in many pathophysiological processes in the nervous system. They can be released from all types of brain cells in the extracellular space and activates purinergic receptors. Signaling via extracellular ATP is regulated by cell-surface located ectonucleotidases. Extracellular AMP resulting from the hydrolysis of ATP and ADP can in turn be hydrolyzed into adenosine by ecto-5'-nucleotidase (eN). We examined the involvement of purinergic signaling components in the rat model of trimethyltin (TMT)-induced hippocampal neurodegeneration (8mg/kg, single ip), which results in behavioral and neurological dysfunction similar as in Alzheimer's disease models. Enzyme histochemistry and immunohistochemistry (ir) showed that products of AMPase activity and eN-ir were accumulated in the neuronal strata, infiltrating within neuronal cell layers, depicting individual round-shaped elements that covered neuronal layers with pronounced cell death mostly at the late stage of TMT-induced neurodegeneration. Co-localization with Iba1+ specifically marked eN at amoeboid microglial cells. Neither of the tested pro-inflammatory cytokines (IL-1β, TNF-α, IL10) and C3 nor polarization marker iNOS was found in association with those Iba1/eN+ -cells. Iba1-ir cells co-localized with Arg1-ir and phagocytic marker CD68- ir. Marked induction of P2Y12R-, P2Y6R-, and P2X4-mRNA at the early stage of TMT-induced neurodegeneration might reflect the migration, and chemotaxis of microglia, while induction of P2X7R at amoeboid cells probably modulates their phagocytic role. These findings may contribute to a better understanding of the involvement of purinergic signaling components in the progression of neurodegenerative disorders that could be target molecules for development of novel therapies.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Ecto-5'-nucleotidase marks amoeboid microglial cells in the rat model of neurodegeneration",
pages = "120",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11061"
}

Grković, I., Dragić, M., Mitrović, N., Zarić Kontić, M., Martinović, J.,& Guševac Stojanović, I.. (2023). Ecto-5'-nucleotidase marks amoeboid microglial cells in the rat model of neurodegeneration. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 120.
https://hdl.handle.net/21.15107/rcub_vinar_11061

Grković I, Dragić M, Mitrović N, Zarić Kontić M, Martinović J, Guševac Stojanović I. Ecto-5'-nucleotidase marks amoeboid microglial cells in the rat model of neurodegeneration. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:120.
https://hdl.handle.net/21.15107/rcub_vinar_11061 .

Grković, Ivana, Dragić, Milorad, Mitrović, Nataša, Zarić Kontić, Marina, Martinović, Jelena, Guševac Stojanović, Ivana, "Ecto-5'-nucleotidase marks amoeboid microglial cells in the rat model of neurodegeneration" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):120,
https://hdl.handle.net/21.15107/rcub_vinar_11061 .

TY  - CONF
AU  - Martinović, Jelena
AU  - Zarić Kontić, Marina
AU  - Guševac Stojanović, Ivana
AU  - Mitrović, Nataša
AU  - Grković, Ivana
AU  - Stojanović, Zoran
AU  - Drakulić, Dunja
AU  - Samardžić, Janko
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11047
AB  - Zaleplon, a member of Z-drugs, is a pyrazolopyrimidine hypnotic with sedative, anxiolytic, anticonvulsant and muscle relaxant properties. Zaleplon is approved for the short-term management of insomnia since acting as positive γ-aminobutyric acid (GABA) receptor allosteric modulator increases efficacy of inhibition on brain excitability. Importantly, for the proper functioning of the brain a balance between inhibitory (i.e., GABAergic) and excitatory (i.e., glutamatergic) system must be accomplished. This may be fulfilled by control of presynaptic elements (synthesis or degradation of glutamate and GABA neurotransmitters, their compartmentation, releasing and recycling) and regulation of expression and function of glutamate and GABA receptors. Hence, we aimed to investigate effects of prolonged zaleplon treatment on the expression of proteins involved in the gabaergic and glutamatergic signalization in the hippocampus of adult male Wistar rats. Five-day intraperitoneal administration increased level of components of GABAergic signalization (glutamate decarboxylase 67-GAD67, vesicular GABA transporter-VGAT and α1 subunit of GABA receptor-GABAAα1). This was accompanied by increased level of glutamatergic components (vesicular glutamate transporter 1-vGlut1 and subunits of glutamate N-Methyl-d-aspartate receptor-NMDAR, namely NR1, NR2A, NR2B), which clearly indicate maintenance of balance between main inhibitory and excitatory neurotransmitters. Given the importance of equilibrium of these systems for neuronal excitability, synaptic plasticity and cognitive functions, as well as its involvement in the mood, feeding behavior, reproductive functions, pain sensitivity, aging, etc., the current and prospective pharmaceuticals increasingly rely on GABA/glutamate balance
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Prolonged zaleplon treatment enhance GABAergic and glutamatergic signaling in the hippocampus of male Wistar rats
SP  - 59
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11047
ER  - 

@conference{
author = "Martinović, Jelena and Zarić Kontić, Marina and Guševac Stojanović, Ivana and Mitrović, Nataša and Grković, Ivana and Stojanović, Zoran and Drakulić, Dunja and Samardžić, Janko",
year = "2023",
abstract = "Zaleplon, a member of Z-drugs, is a pyrazolopyrimidine hypnotic with sedative, anxiolytic, anticonvulsant and muscle relaxant properties. Zaleplon is approved for the short-term management of insomnia since acting as positive γ-aminobutyric acid (GABA) receptor allosteric modulator increases efficacy of inhibition on brain excitability. Importantly, for the proper functioning of the brain a balance between inhibitory (i.e., GABAergic) and excitatory (i.e., glutamatergic) system must be accomplished. This may be fulfilled by control of presynaptic elements (synthesis or degradation of glutamate and GABA neurotransmitters, their compartmentation, releasing and recycling) and regulation of expression and function of glutamate and GABA receptors. Hence, we aimed to investigate effects of prolonged zaleplon treatment on the expression of proteins involved in the gabaergic and glutamatergic signalization in the hippocampus of adult male Wistar rats. Five-day intraperitoneal administration increased level of components of GABAergic signalization (glutamate decarboxylase 67-GAD67, vesicular GABA transporter-VGAT and α1 subunit of GABA receptor-GABAAα1). This was accompanied by increased level of glutamatergic components (vesicular glutamate transporter 1-vGlut1 and subunits of glutamate N-Methyl-d-aspartate receptor-NMDAR, namely NR1, NR2A, NR2B), which clearly indicate maintenance of balance between main inhibitory and excitatory neurotransmitters. Given the importance of equilibrium of these systems for neuronal excitability, synaptic plasticity and cognitive functions, as well as its involvement in the mood, feeding behavior, reproductive functions, pain sensitivity, aging, etc., the current and prospective pharmaceuticals increasingly rely on GABA/glutamate balance",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Prolonged zaleplon treatment enhance GABAergic and glutamatergic signaling in the hippocampus of male Wistar rats",
pages = "59",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11047"
}

Martinović, J., Zarić Kontić, M., Guševac Stojanović, I., Mitrović, N., Grković, I., Stojanović, Z., Drakulić, D.,& Samardžić, J.. (2023). Prolonged zaleplon treatment enhance GABAergic and glutamatergic signaling in the hippocampus of male Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 59.
https://hdl.handle.net/21.15107/rcub_vinar_11047

Martinović J, Zarić Kontić M, Guševac Stojanović I, Mitrović N, Grković I, Stojanović Z, Drakulić D, Samardžić J. Prolonged zaleplon treatment enhance GABAergic and glutamatergic signaling in the hippocampus of male Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:59.
https://hdl.handle.net/21.15107/rcub_vinar_11047 .

Martinović, Jelena, Zarić Kontić, Marina, Guševac Stojanović, Ivana, Mitrović, Nataša, Grković, Ivana, Stojanović, Zoran, Drakulić, Dunja, Samardžić, Janko, "Prolonged zaleplon treatment enhance GABAergic and glutamatergic signaling in the hippocampus of male Wistar rats" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):59,
https://hdl.handle.net/21.15107/rcub_vinar_11047 .

TY  - CONF
AU  - Zarić Kontić, Marina
AU  - Dragić, Milorad
AU  - Martinović, Jelena
AU  - Mihajlović, Katarina
AU  - Brkić, Željka
AU  - Mitrović, Nataša
AU  - Guševac Stojanović, Ivana
AU  - Grković, Ivana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11048
AB  - The benzodiazepine alprazolam (ALP) is commonly prescribed to treat anxiety, panic, and sleep disorders. However, ALP is often abused for prolonged periods of time, leading to severe side effects such as tolerance, dependence, and withdrawal syndrome. Previous literature data suggest that neuroadaptive changes at synaptic receptors, such as gammaaminobutyric acid receptor type A (GABAAR) and glutamatergic receptors, may be responsible for the occurrence and development of the aforementioned side effects. Therefore, the present study investigated the potential effects of prolonged ALP treatment (2 mg/kg, ip.) on the α1-subunit containing GABAAR and components of glutamatergic neurotransmission in the hippocampus of adult male Wistar rats. The study revealed behavioral changes consistent with a possible onset of tolerance and associated changes in the GABAergic and glutamatergic systems. The primary target of ALP, the α1-subunit containing GABAAR, was decreased indicating its potential downregulation by prolonged agonist (ALP) action. Considering studied glutamatergic components, an increase in NMDAR subunits, a decrease in vGlut1, and differential modulation of excitatory amino acid transporters 1 and 2 (EAAT1/2, in vivo and in vitro) were observed. These changes may all together indicate a compensatory mechanism due to the sustained suppression of glutamatergic neurons by enhanced inhibitory impulses from GABAergic neurons. The data presented provide valuable and, to our knowledge, the first information on components of glutamatergic neurotransmission after prolonged ALP treatment and their potential impact on the development of side effects. However, further research is needed to examine the observed changes in detail.
PB  - Belgrade : Serbian Neurocardiological Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Long-term alprazolam treatment may cause tolerance development by modulating components of glutamatergic neurotransmission in the hippocampus of male Wistar rats
SP  - 60
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11048
ER  - 

@conference{
author = "Zarić Kontić, Marina and Dragić, Milorad and Martinović, Jelena and Mihajlović, Katarina and Brkić, Željka and Mitrović, Nataša and Guševac Stojanović, Ivana and Grković, Ivana",
year = "2023",
abstract = "The benzodiazepine alprazolam (ALP) is commonly prescribed to treat anxiety, panic, and sleep disorders. However, ALP is often abused for prolonged periods of time, leading to severe side effects such as tolerance, dependence, and withdrawal syndrome. Previous literature data suggest that neuroadaptive changes at synaptic receptors, such as gammaaminobutyric acid receptor type A (GABAAR) and glutamatergic receptors, may be responsible for the occurrence and development of the aforementioned side effects. Therefore, the present study investigated the potential effects of prolonged ALP treatment (2 mg/kg, ip.) on the α1-subunit containing GABAAR and components of glutamatergic neurotransmission in the hippocampus of adult male Wistar rats. The study revealed behavioral changes consistent with a possible onset of tolerance and associated changes in the GABAergic and glutamatergic systems. The primary target of ALP, the α1-subunit containing GABAAR, was decreased indicating its potential downregulation by prolonged agonist (ALP) action. Considering studied glutamatergic components, an increase in NMDAR subunits, a decrease in vGlut1, and differential modulation of excitatory amino acid transporters 1 and 2 (EAAT1/2, in vivo and in vitro) were observed. These changes may all together indicate a compensatory mechanism due to the sustained suppression of glutamatergic neurons by enhanced inhibitory impulses from GABAergic neurons. The data presented provide valuable and, to our knowledge, the first information on components of glutamatergic neurotransmission after prolonged ALP treatment and their potential impact on the development of side effects. However, further research is needed to examine the observed changes in detail.",
publisher = "Belgrade : Serbian Neurocardiological Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Long-term alprazolam treatment may cause tolerance development by modulating components of glutamatergic neurotransmission in the hippocampus of male Wistar rats",
pages = "60",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11048"
}

Zarić Kontić, M., Dragić, M., Martinović, J., Mihajlović, K., Brkić, Ž., Mitrović, N., Guševac Stojanović, I.,& Grković, I.. (2023). Long-term alprazolam treatment may cause tolerance development by modulating components of glutamatergic neurotransmission in the hippocampus of male Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neurocardiological Society., 60.
https://hdl.handle.net/21.15107/rcub_vinar_11048

Zarić Kontić M, Dragić M, Martinović J, Mihajlović K, Brkić Ž, Mitrović N, Guševac Stojanović I, Grković I. Long-term alprazolam treatment may cause tolerance development by modulating components of glutamatergic neurotransmission in the hippocampus of male Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:60.
https://hdl.handle.net/21.15107/rcub_vinar_11048 .

Zarić Kontić, Marina, Dragić, Milorad, Martinović, Jelena, Mihajlović, Katarina, Brkić, Željka, Mitrović, Nataša, Guševac Stojanović, Ivana, Grković, Ivana, "Long-term alprazolam treatment may cause tolerance development by modulating components of glutamatergic neurotransmission in the hippocampus of male Wistar rats" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):60,
https://hdl.handle.net/21.15107/rcub_vinar_11048 .

TY  - CONF
AU  - Mitrović, Nataša
AU  - Zarić, Marina
AU  - Martinović, Jelena
AU  - Guševac Stojanović, Ivana
AU  - Petrović, Snježana
AU  - Paunović, Marija
AU  - Vučić, Vesna
AU  - Grković, Ivana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11050
AB  - It is increasingly apparent that the prevention/treatment of neurodegenerative disorders is not only achieved through pharmacological therapy but also through the consumption of natural products. Flaxseed oil (or linseed oil, FSO) derived from the seeds of the flax (Linum usitatissimum L.) gained worldwide awareness as a neuroprotective agent due to its high content of omega-3 polyunsaturated fatty acids (n-3 PUFAs). Thus, the aim of this study was to examine the preventive effects of dietary FSO in trimethyltin (TMT) - induced hippocampal neurodegeneration and gliosis in female Wistar rats. Animals were continuously treated with FSO (1 ml/kg, orally) for two weeks, then received a single dose of TMT (8 mg/kg, i.p.), and application of FSO continued for twenty-one days. Data have convincingly shown that FSO continuous treatment ameliorated TMT-induced neuronal loss in the CA3 hippocampal region and ameliorated astrogliosis and microgliosis. FSO treatment elevated all tested n-3 fatty acids in the hippocampus: α-linolenic acid (ALA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), and consequently increased total amount of n-3 PUFA. However, no changes in n-6 fatty acids due to FSO treatment were observed. Consequently, FSO lowered n-6/n-3 ratio compared to TMT, having a protective effect on fatty acid profile in hippocampus. These findings support beneficial neuroprotective properties of FSO against TMT-induced model of neurodegeneration and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction
PB  - Belgrade : Serbian Neurocardiological Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Dietary supplementation with flaxseed oil ameliorates trimethyltin (TMT)-induced neurodegeneration and gliosis in female Wistar rats
SP  - 81
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11050
ER  - 

@conference{
author = "Mitrović, Nataša and Zarić, Marina and Martinović, Jelena and Guševac Stojanović, Ivana and Petrović, Snježana and Paunović, Marija and Vučić, Vesna and Grković, Ivana",
year = "2023",
abstract = "It is increasingly apparent that the prevention/treatment of neurodegenerative disorders is not only achieved through pharmacological therapy but also through the consumption of natural products. Flaxseed oil (or linseed oil, FSO) derived from the seeds of the flax (Linum usitatissimum L.) gained worldwide awareness as a neuroprotective agent due to its high content of omega-3 polyunsaturated fatty acids (n-3 PUFAs). Thus, the aim of this study was to examine the preventive effects of dietary FSO in trimethyltin (TMT) - induced hippocampal neurodegeneration and gliosis in female Wistar rats. Animals were continuously treated with FSO (1 ml/kg, orally) for two weeks, then received a single dose of TMT (8 mg/kg, i.p.), and application of FSO continued for twenty-one days. Data have convincingly shown that FSO continuous treatment ameliorated TMT-induced neuronal loss in the CA3 hippocampal region and ameliorated astrogliosis and microgliosis. FSO treatment elevated all tested n-3 fatty acids in the hippocampus: α-linolenic acid (ALA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), and consequently increased total amount of n-3 PUFA. However, no changes in n-6 fatty acids due to FSO treatment were observed. Consequently, FSO lowered n-6/n-3 ratio compared to TMT, having a protective effect on fatty acid profile in hippocampus. These findings support beneficial neuroprotective properties of FSO against TMT-induced model of neurodegeneration and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction",
publisher = "Belgrade : Serbian Neurocardiological Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Dietary supplementation with flaxseed oil ameliorates trimethyltin (TMT)-induced neurodegeneration and gliosis in female Wistar rats",
pages = "81",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11050"
}

Mitrović, N., Zarić, M., Martinović, J., Guševac Stojanović, I., Petrović, S., Paunović, M., Vučić, V.,& Grković, I.. (2023). Dietary supplementation with flaxseed oil ameliorates trimethyltin (TMT)-induced neurodegeneration and gliosis in female Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neurocardiological Society., 81.
https://hdl.handle.net/21.15107/rcub_vinar_11050

Mitrović N, Zarić M, Martinović J, Guševac Stojanović I, Petrović S, Paunović M, Vučić V, Grković I. Dietary supplementation with flaxseed oil ameliorates trimethyltin (TMT)-induced neurodegeneration and gliosis in female Wistar rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:81.
https://hdl.handle.net/21.15107/rcub_vinar_11050 .

Mitrović, Nataša, Zarić, Marina, Martinović, Jelena, Guševac Stojanović, Ivana, Petrović, Snježana, Paunović, Marija, Vučić, Vesna, Grković, Ivana, "Dietary supplementation with flaxseed oil ameliorates trimethyltin (TMT)-induced neurodegeneration and gliosis in female Wistar rats" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):81,
https://hdl.handle.net/21.15107/rcub_vinar_11050 .

TY  - JOUR
AU  - Martinović, Jelena
AU  - Zarić Kontić, Marina
AU  - Dragić, Milorad
AU  - Todorović, Ana
AU  - Guševac Stojanović, Ivana
AU  - Mitrović, Nataša
AU  - Grković, Ivana
AU  - Drakulić, Dunja R.
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10461
AB  - D-galactose (d-gal) is broadly used in animal aging studies as its chronic administration mimics learning and memory impairments related to aging in humans. However, within the few studies that utilize chronic oral d-gal intake, none of them is focused on alteration in synaptic structure and function. We examined the effects of 6-weeks oral d-gal intake (200 mg/kg and 500 mg/kg, dissolved in tap water) on age-related changes, with emphasis on the prefrontal cortex (PFC) and hippocampus (HIP) of adult male Wistar rats. Memory assessment was followed by histological examination of the PFC and HIP (Nissl staining and Iba-1 immunostaining), while in crude synaptosomal fractions the state of oxidative stress and the expression of proteins involved in glutamatergic signaling was determined. Although applied dosages compromised memory, alterations such as impaired sensory-motor function and aberrant morphology were not detected. In the PFC, analysis of microglia revealed reduction of branching pattern following d-gal intake, in parallel with increased oxidative damage of proteins, lipids and disturbed pro-oxidant antioxidant balance. These changes in the PFC were further accompanied with decreased levels of vesicular glutamate transporter 1, syntaxin-1 and NMDA receptor 2B subunit in both treated groups. Simultaneously, the increased hippocampal oxidative damage of lipids was detected. Results indicate successful provocation of age-related changes following oral d-gal intake, and suggest greater sensitivity of the PFC to d-gal treatment than HIP.
T2  - Behavioural Brain Research
T1  - Chronic oral d-galactose intake provokes age-related changes in the rat prefrontal cortex
VL  - 436
SP  - 114072
DO  - 10.1016/j.bbr.2022.114072
ER  - 

@article{
author = "Martinović, Jelena and Zarić Kontić, Marina and Dragić, Milorad and Todorović, Ana and Guševac Stojanović, Ivana and Mitrović, Nataša and Grković, Ivana and Drakulić, Dunja R.",
year = "2023",
abstract = "D-galactose (d-gal) is broadly used in animal aging studies as its chronic administration mimics learning and memory impairments related to aging in humans. However, within the few studies that utilize chronic oral d-gal intake, none of them is focused on alteration in synaptic structure and function. We examined the effects of 6-weeks oral d-gal intake (200 mg/kg and 500 mg/kg, dissolved in tap water) on age-related changes, with emphasis on the prefrontal cortex (PFC) and hippocampus (HIP) of adult male Wistar rats. Memory assessment was followed by histological examination of the PFC and HIP (Nissl staining and Iba-1 immunostaining), while in crude synaptosomal fractions the state of oxidative stress and the expression of proteins involved in glutamatergic signaling was determined. Although applied dosages compromised memory, alterations such as impaired sensory-motor function and aberrant morphology were not detected. In the PFC, analysis of microglia revealed reduction of branching pattern following d-gal intake, in parallel with increased oxidative damage of proteins, lipids and disturbed pro-oxidant antioxidant balance. These changes in the PFC were further accompanied with decreased levels of vesicular glutamate transporter 1, syntaxin-1 and NMDA receptor 2B subunit in both treated groups. Simultaneously, the increased hippocampal oxidative damage of lipids was detected. Results indicate successful provocation of age-related changes following oral d-gal intake, and suggest greater sensitivity of the PFC to d-gal treatment than HIP.",
journal = "Behavioural Brain Research",
title = "Chronic oral d-galactose intake provokes age-related changes in the rat prefrontal cortex",
volume = "436",
pages = "114072",
doi = "10.1016/j.bbr.2022.114072"
}

Martinović, J., Zarić Kontić, M., Dragić, M., Todorović, A., Guševac Stojanović, I., Mitrović, N., Grković, I.,& Drakulić, D. R.. (2023). Chronic oral d-galactose intake provokes age-related changes in the rat prefrontal cortex. in Behavioural Brain Research, 436, 114072.
https://doi.org/10.1016/j.bbr.2022.114072

Martinović J, Zarić Kontić M, Dragić M, Todorović A, Guševac Stojanović I, Mitrović N, Grković I, Drakulić DR. Chronic oral d-galactose intake provokes age-related changes in the rat prefrontal cortex. in Behavioural Brain Research. 2023;436:114072.
doi:10.1016/j.bbr.2022.114072 .

Martinović, Jelena, Zarić Kontić, Marina, Dragić, Milorad, Todorović, Ana, Guševac Stojanović, Ivana, Mitrović, Nataša, Grković, Ivana, Drakulić, Dunja R., "Chronic oral d-galactose intake provokes age-related changes in the rat prefrontal cortex" in Behavioural Brain Research, 436 (2023):114072,
https://doi.org/10.1016/j.bbr.2022.114072 . .

TY  - JOUR
AU  - Zarić Kontić, Marina
AU  - Dragić, Milorad
AU  - Martinović, Jelena
AU  - Mihajlović, Katarina
AU  - Brkić, Željka
AU  - Mitrović, Nataša
AU  - Grković, Ivana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11160
AB  - Alprazolam (ALP), a benzodiazepine (BDZ) used to treat anxiety, panic, and sleep disorders, is one of the most prescribed psychotropic drugs worldwide. The side effects associated with long-term (mis)use of ALP have become a major challenge in pharmacotherapy, emphasizing the unmet need to further investigate their underlying molecular mechanisms. Prolonged BDZ exposure may induce adaptive changes in the function of several receptors, including the primary target, gammaaminobutyric acid receptor type A (GABAAR), but also other neurotransmitter receptors such as glutamatergic. The present study investigated the potential effects of prolonged ALP treatment on components of glutamatergic neurotransmission, with special emphasis on N-Methyl-D-aspartate receptor (NMDAR) in the hippocampus of adult male Wistar rats. The study revealed behavioral changes consistent with potential onset of tolerance and involvement of the glutamatergic system in its development. Specifically, an increase in NMDAR subunits (NR1, NR2A, NR2B), a decrease in vesicular glutamate transporter 1 (vGlut1), and differential modulation of excitatory amino acid transporters 1 and 2 (EAAT1/2, in vivo and in vitro) were observed, alongside a decrease in α1-containing GABAAR following the treatment. By describing the development of compensatory actions in the glutamatergic system, the present study provides valuable information on neuroadaptive mechanisms following prolonged ALP intake.
T2  - Pharmaceuticals
T1  - Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use
VL  - 16
IS  - 3
SP  - 331
DO  - 10.3390/ph16030331
ER  - 

@article{
author = "Zarić Kontić, Marina and Dragić, Milorad and Martinović, Jelena and Mihajlović, Katarina and Brkić, Željka and Mitrović, Nataša and Grković, Ivana",
year = "2023",
abstract = "Alprazolam (ALP), a benzodiazepine (BDZ) used to treat anxiety, panic, and sleep disorders, is one of the most prescribed psychotropic drugs worldwide. The side effects associated with long-term (mis)use of ALP have become a major challenge in pharmacotherapy, emphasizing the unmet need to further investigate their underlying molecular mechanisms. Prolonged BDZ exposure may induce adaptive changes in the function of several receptors, including the primary target, gammaaminobutyric acid receptor type A (GABAAR), but also other neurotransmitter receptors such as glutamatergic. The present study investigated the potential effects of prolonged ALP treatment on components of glutamatergic neurotransmission, with special emphasis on N-Methyl-D-aspartate receptor (NMDAR) in the hippocampus of adult male Wistar rats. The study revealed behavioral changes consistent with potential onset of tolerance and involvement of the glutamatergic system in its development. Specifically, an increase in NMDAR subunits (NR1, NR2A, NR2B), a decrease in vesicular glutamate transporter 1 (vGlut1), and differential modulation of excitatory amino acid transporters 1 and 2 (EAAT1/2, in vivo and in vitro) were observed, alongside a decrease in α1-containing GABAAR following the treatment. By describing the development of compensatory actions in the glutamatergic system, the present study provides valuable information on neuroadaptive mechanisms following prolonged ALP intake.",
journal = "Pharmaceuticals",
title = "Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use",
volume = "16",
number = "3",
pages = "331",
doi = "10.3390/ph16030331"
}

Zarić Kontić, M., Dragić, M., Martinović, J., Mihajlović, K., Brkić, Ž., Mitrović, N.,& Grković, I.. (2023). Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use. in Pharmaceuticals, 16(3), 331.
https://doi.org/10.3390/ph16030331

Zarić Kontić M, Dragić M, Martinović J, Mihajlović K, Brkić Ž, Mitrović N, Grković I. Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use. in Pharmaceuticals. 2023;16(3):331.
doi:10.3390/ph16030331 .

Zarić Kontić, Marina, Dragić, Milorad, Martinović, Jelena, Mihajlović, Katarina, Brkić, Željka, Mitrović, Nataša, Grković, Ivana, "Prolonged Alprazolam Treatment Alters Components of Glutamatergic Neurotransmission in the Hippocampus of Male Wistar Rats—The Neuroadaptive Changes following Long-Term Benzodiazepine (Mis)Use" in Pharmaceuticals, 16, no. 3 (2023):331,
https://doi.org/10.3390/ph16030331 . .

TY  - JOUR
AU  - Stekić, Anđela
AU  - Zeljković, Milica
AU  - Zarić Kontić, Marina
AU  - Mihajlović, Katarina
AU  - Adžić, Marija
AU  - Stevanović, Ivana
AU  - Ninković, Milica
AU  - Grković, Ivana
AU  - Ilić, Tihomir V.
AU  - Nedeljković, Nadežda
AU  - Dragić, Milorad
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11159
AB  - Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.
T2  - Frontiers in Aging Neuroscience
T1  - Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model
VL  - 14
DO  - 10.3389/fnagi.2022.889983
ER  - 

@article{
author = "Stekić, Anđela and Zeljković, Milica and Zarić Kontić, Marina and Mihajlović, Katarina and Adžić, Marija and Stevanović, Ivana and Ninković, Milica and Grković, Ivana and Ilić, Tihomir V. and Nedeljković, Nadežda and Dragić, Milorad",
year = "2022",
abstract = "Neurodegeneration implies progressive neuronal loss and neuroinflammation further contributing to pathology progression. It is a feature of many neurological disorders, most common being Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive stimulation which modulates excitability of stimulated brain areas through magnetic pulses. Numerous studies indicated beneficial effect of rTMS in several neurological diseases, including AD, however, exact mechanism are yet to be elucidated. We aimed to evaluate the effect of intermittent theta burst stimulation (iTBS), an rTMS paradigm, on behavioral, neurochemical and molecular level in trimethyltin (TMT)-induced Alzheimer’s-like disease model. TMT acts as a neurotoxic agent targeting hippocampus causing cognitive impairment and neuroinflammation, replicating behavioral and molecular aspects of AD. Male Wistar rats were divided into four experimental groups–controls, rats subjected to a single dose of TMT (8 mg/kg), TMT rats subjected to iTBS two times per day for 15 days and TMT sham group. After 3 weeks, we examined exploratory behavior and memory, histopathological and changes on molecular level. TMT-treated rats exhibited severe and cognitive deficit. iTBS-treated animals showed improved cognition. iTBS reduced TMT-induced inflammation and increased anti-inflammatory molecules. We examined PI3K/Akt/mTOR signaling pathway which is involved in regulation of apoptosis, cell growth and learning and memory. We found significant downregulation of phosphorylated forms of Akt and mTOR in TMT-intoxicated animals, which were reverted following iTBS stimulation. Application of iTBS produces beneficial effects on cognition in of rats with TMT-induced hippocampal neurodegeneration and that effect could be mediated via PI3K/Akt/mTOR signaling pathway, which could candidate this protocol as a potential therapeutic approach in neurodegenerative diseases such as AD.",
journal = "Frontiers in Aging Neuroscience",
title = "Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model",
volume = "14",
doi = "10.3389/fnagi.2022.889983"
}

Stekić, A., Zeljković, M., Zarić Kontić, M., Mihajlović, K., Adžić, M., Stevanović, I., Ninković, M., Grković, I., Ilić, T. V., Nedeljković, N.,& Dragić, M.. (2022). Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model. in Frontiers in Aging Neuroscience, 14.
https://doi.org/10.3389/fnagi.2022.889983

Stekić A, Zeljković M, Zarić Kontić M, Mihajlović K, Adžić M, Stevanović I, Ninković M, Grković I, Ilić TV, Nedeljković N, Dragić M. Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model. in Frontiers in Aging Neuroscience. 2022;14.
doi:10.3389/fnagi.2022.889983 .

Stekić, Anđela, Zeljković, Milica, Zarić Kontić, Marina, Mihajlović, Katarina, Adžić, Marija, Stevanović, Ivana, Ninković, Milica, Grković, Ivana, Ilić, Tihomir V., Nedeljković, Nadežda, Dragić, Milorad, "Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model" in Frontiers in Aging Neuroscience, 14 (2022),
https://doi.org/10.3389/fnagi.2022.889983 . .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Stekić, Anđela
AU  - Zeljković, Milica
AU  - Zarić Kontić, Marina
AU  - Mihajlović, Katarina
AU  - Adžić, Marija
AU  - Grković, Ivana
AU  - Nedeljković, Nadežda
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10222
AB  - The present study demonstrates altered topographic distribution and enhanced neuronal expression of major adenosine-metabolizing enzymes, i.e. ecto-5ʹ-nucleotidase (eN) and tissue non-specific alkaline phosphatase (TNAP), as well as adenosine receptor subtype A2A in the hippocampus and cortex of male rats from early to late adulthood (3, 6, 12 and 15 months old males). The significant effect of age was demonstrated for the increase in the activity and the protein expression of eN and TNAP. At 15-m, enzyme histochemistry demonstrated enhanced expression of eN in synapse-rich hippocampal and cortical layers, whereas the upsurge of TNAP was observed in the hippocampal and cortical neuropil, rather than in cells and layers where two enzymes mostly reside in 3-m old brain. Furthermore, a dichotomy in A1R and A2AR expression was demonstrated in the cortex and hippocampus from early to late adulthood. Specifically, a decrease in A1R and enhancement of A2AR expression were demonstrated by immunohistochemistry, the latter being almost exclusively localized in hippocampal pyramidal and cortical superficial cell layers. We did not observe any glial upregulation of A2AR, which was common for both advanced age and chronic neurodegeneration. Taken together, the results imply that the adaptative changes in adenosine signaling occurring in neuronal elements early in life may be responsible for the later prominent glial enhancement in A2AR-mediated adenosine signaling, and neuroinflammation and neurodegeneration, which are the hallmarks of both advanced age and age-associated neurodegenerative diseases.
T2  - Neurochemical Research
T1  - Altered Topographic Distribution and Enhanced Neuronal Expression of Adenosine-Metabolizing Enzymes in Rat Hippocampus and Cortex from Early to late Adulthood
DO  - 10.1007/s11064-022-03557-5
ER  - 

@article{
author = "Dragić, Milorad and Stekić, Anđela and Zeljković, Milica and Zarić Kontić, Marina and Mihajlović, Katarina and Adžić, Marija and Grković, Ivana and Nedeljković, Nadežda",
year = "2022",
abstract = "The present study demonstrates altered topographic distribution and enhanced neuronal expression of major adenosine-metabolizing enzymes, i.e. ecto-5ʹ-nucleotidase (eN) and tissue non-specific alkaline phosphatase (TNAP), as well as adenosine receptor subtype A2A in the hippocampus and cortex of male rats from early to late adulthood (3, 6, 12 and 15 months old males). The significant effect of age was demonstrated for the increase in the activity and the protein expression of eN and TNAP. At 15-m, enzyme histochemistry demonstrated enhanced expression of eN in synapse-rich hippocampal and cortical layers, whereas the upsurge of TNAP was observed in the hippocampal and cortical neuropil, rather than in cells and layers where two enzymes mostly reside in 3-m old brain. Furthermore, a dichotomy in A1R and A2AR expression was demonstrated in the cortex and hippocampus from early to late adulthood. Specifically, a decrease in A1R and enhancement of A2AR expression were demonstrated by immunohistochemistry, the latter being almost exclusively localized in hippocampal pyramidal and cortical superficial cell layers. We did not observe any glial upregulation of A2AR, which was common for both advanced age and chronic neurodegeneration. Taken together, the results imply that the adaptative changes in adenosine signaling occurring in neuronal elements early in life may be responsible for the later prominent glial enhancement in A2AR-mediated adenosine signaling, and neuroinflammation and neurodegeneration, which are the hallmarks of both advanced age and age-associated neurodegenerative diseases.",
journal = "Neurochemical Research",
title = "Altered Topographic Distribution and Enhanced Neuronal Expression of Adenosine-Metabolizing Enzymes in Rat Hippocampus and Cortex from Early to late Adulthood",
doi = "10.1007/s11064-022-03557-5"
}

Dragić, M., Stekić, A., Zeljković, M., Zarić Kontić, M., Mihajlović, K., Adžić, M., Grković, I.,& Nedeljković, N.. (2022). Altered Topographic Distribution and Enhanced Neuronal Expression of Adenosine-Metabolizing Enzymes in Rat Hippocampus and Cortex from Early to late Adulthood. in Neurochemical Research.
https://doi.org/10.1007/s11064-022-03557-5

Dragić M, Stekić A, Zeljković M, Zarić Kontić M, Mihajlović K, Adžić M, Grković I, Nedeljković N. Altered Topographic Distribution and Enhanced Neuronal Expression of Adenosine-Metabolizing Enzymes in Rat Hippocampus and Cortex from Early to late Adulthood. in Neurochemical Research. 2022;.
doi:10.1007/s11064-022-03557-5 .

Dragić, Milorad, Stekić, Anđela, Zeljković, Milica, Zarić Kontić, Marina, Mihajlović, Katarina, Adžić, Marija, Grković, Ivana, Nedeljković, Nadežda, "Altered Topographic Distribution and Enhanced Neuronal Expression of Adenosine-Metabolizing Enzymes in Rat Hippocampus and Cortex from Early to late Adulthood" in Neurochemical Research (2022),
https://doi.org/10.1007/s11064-022-03557-5 . .

TY  - JOUR
AU  - Grković, Ivana
AU  - Mitrović, Nataša
AU  - Dragić, Milorad
AU  - Zarić Kontić, Marina
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10519
AB  - Adenosine 5'-triphosphate (ATP) and other nucleotides and nucleosides, such as adenosine, are versatile signaling molecules involved in many physiological processes and pathological conditions in the nervous system, especially those with an inflammatory component. They can be released from nerve cells, glial cells, and vascular cells into the extracellular space where they exert their function via ionotropic (P2X) or metabotropic (P2Y) receptors. Signaling via extracellular nucleotides and adenosine is regulated by cell-surface located enzymes ectonucleotidases that hydrolyze the nucleotide to the respective nucleoside. This review summarizes a histochemical approach for detection of ectonucleotidase activities in the cryo-sections of brain tissue. The enzyme histochemistry (EHC) might be used as suitable replacement for immunohistochemistry, since it gives information about both localization and activity, thus adding a functional component to a classical histological approach. With this technique, it is possible to visualize spatial distribution and cell-specific localization of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5'-nucleotidase (eN/CD73) activities during brain development, after different hormonal manipulations, during neurodegeneration, etc. EHC is also suitable for investigation of microglial morphology in different (patho)physiological conditions. Furthermore, the review describes how to quantify EHC results.
T2  - Histology and Histopathology
T1  - Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions
VL  - 37
IS  - 10
SP  - 919
EP  - 936
DO  - 10.14670/HH-18-471
ER  - 

@article{
author = "Grković, Ivana and Mitrović, Nataša and Dragić, Milorad and Zarić Kontić, Marina",
year = "2022",
abstract = "Adenosine 5'-triphosphate (ATP) and other nucleotides and nucleosides, such as adenosine, are versatile signaling molecules involved in many physiological processes and pathological conditions in the nervous system, especially those with an inflammatory component. They can be released from nerve cells, glial cells, and vascular cells into the extracellular space where they exert their function via ionotropic (P2X) or metabotropic (P2Y) receptors. Signaling via extracellular nucleotides and adenosine is regulated by cell-surface located enzymes ectonucleotidases that hydrolyze the nucleotide to the respective nucleoside. This review summarizes a histochemical approach for detection of ectonucleotidase activities in the cryo-sections of brain tissue. The enzyme histochemistry (EHC) might be used as suitable replacement for immunohistochemistry, since it gives information about both localization and activity, thus adding a functional component to a classical histological approach. With this technique, it is possible to visualize spatial distribution and cell-specific localization of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5'-nucleotidase (eN/CD73) activities during brain development, after different hormonal manipulations, during neurodegeneration, etc. EHC is also suitable for investigation of microglial morphology in different (patho)physiological conditions. Furthermore, the review describes how to quantify EHC results.",
journal = "Histology and Histopathology",
title = "Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions",
volume = "37",
number = "10",
pages = "919-936",
doi = "10.14670/HH-18-471"
}

Grković, I., Mitrović, N., Dragić, M.,& Zarić Kontić, M.. (2022). Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions. in Histology and Histopathology, 37(10), 919-936.
https://doi.org/10.14670/HH-18-471

Grković I, Mitrović N, Dragić M, Zarić Kontić M. Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions. in Histology and Histopathology. 2022;37(10):919-936.
doi:10.14670/HH-18-471 .

Grković, Ivana, Mitrović, Nataša, Dragić, Milorad, Zarić Kontić, Marina, "Enzyme histochemistry: a useful tool for examining the spatial distribution of brain ectonucleotidases in (patho)physiological conditions" in Histology and Histopathology, 37, no. 10 (2022):919-936,
https://doi.org/10.14670/HH-18-471 . .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Mitrović, Nataša Lj.
AU  - Adžić, Marija
AU  - Nedeljković, Nadežda
AU  - Grković, Ivana
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9970
AB  - The present study examined the involvement of purinergic signaling components in the rat model of hippocampal degeneration induced by trimethyltin (TMT) intoxication (8 mg/kg, single intraperitoneal injection), which results in behavioral and neurological dysfunction similar to neurodegenerative disorders. We investigated spatial and temporal patterns of ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5′ nucleotidase (eN/CD73) activity, their cell-specific localization, and analyzed gene expression pattern and/or cellular localization of purinoreceptors and proinflammatory mediators associated with reactive glial cells. Our study demonstrated that all Iba1+ cells at the injured area, irrespective of their morphology, upregulated NTPDase1/CD39, while induction of eN/CD73 has been observed at amoeboid Iba1+ cells localized within the hippocampal neuronal layers with pronounced cell death. Marked induction of P2Y12R, P2Y6R, and P2X4-messenger RNA at the early stage of TMT-induced neurodegeneration might reflect the functional properties, migration, and chemotaxis of microglia, while induction of P2X7R at amoeboid cells probably modulates their phagocytic role. Reactive astrocytes expressed adenosine A1, A2A, and P2Y1 receptors, revealed induction of complement component C3, inducible nitric oxide synthase, nuclear factor-kB, and proinflammatory cytokines at the late stage of TMT-induced neurodegeneration. An increased set of purinergic system components on activated microglia (NTPDase1/CD39, eN/CD73, and P2X7) and astrocytes (A1R, A2AR, and P2Y1), and loss of homeostatic glial and neuronal purinergic pathways (P2Y12 and A1R) may shift purinergic signaling balance toward excitotoxicity and inflammation, thus favoring progression of pathological events. These findings may contribute to a better understanding of the involvement of purinergic signaling components in the progression of neurodegenerative disorders that could be target molecules for the development of novel therapies.
T2  - ASN Neuro
T1  - Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration
VL  - 13
SP  - 17590914211044882
DO  - 10.1177/17590914211044882
ER  - 

@article{
author = "Dragić, Milorad and Mitrović, Nataša Lj. and Adžić, Marija and Nedeljković, Nadežda and Grković, Ivana",
year = "2021",
abstract = "The present study examined the involvement of purinergic signaling components in the rat model of hippocampal degeneration induced by trimethyltin (TMT) intoxication (8 mg/kg, single intraperitoneal injection), which results in behavioral and neurological dysfunction similar to neurodegenerative disorders. We investigated spatial and temporal patterns of ecto-nucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5′ nucleotidase (eN/CD73) activity, their cell-specific localization, and analyzed gene expression pattern and/or cellular localization of purinoreceptors and proinflammatory mediators associated with reactive glial cells. Our study demonstrated that all Iba1+ cells at the injured area, irrespective of their morphology, upregulated NTPDase1/CD39, while induction of eN/CD73 has been observed at amoeboid Iba1+ cells localized within the hippocampal neuronal layers with pronounced cell death. Marked induction of P2Y12R, P2Y6R, and P2X4-messenger RNA at the early stage of TMT-induced neurodegeneration might reflect the functional properties, migration, and chemotaxis of microglia, while induction of P2X7R at amoeboid cells probably modulates their phagocytic role. Reactive astrocytes expressed adenosine A1, A2A, and P2Y1 receptors, revealed induction of complement component C3, inducible nitric oxide synthase, nuclear factor-kB, and proinflammatory cytokines at the late stage of TMT-induced neurodegeneration. An increased set of purinergic system components on activated microglia (NTPDase1/CD39, eN/CD73, and P2X7) and astrocytes (A1R, A2AR, and P2Y1), and loss of homeostatic glial and neuronal purinergic pathways (P2Y12 and A1R) may shift purinergic signaling balance toward excitotoxicity and inflammation, thus favoring progression of pathological events. These findings may contribute to a better understanding of the involvement of purinergic signaling components in the progression of neurodegenerative disorders that could be target molecules for the development of novel therapies.",
journal = "ASN Neuro",
title = "Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration",
volume = "13",
pages = "17590914211044882",
doi = "10.1177/17590914211044882"
}

Dragić, M., Mitrović, N. Lj., Adžić, M., Nedeljković, N.,& Grković, I.. (2021). Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration. in ASN Neuro, 13, 17590914211044882.
https://doi.org/10.1177/17590914211044882

Dragić M, Mitrović NL, Adžić M, Nedeljković N, Grković I. Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration. in ASN Neuro. 2021;13:17590914211044882.
doi:10.1177/17590914211044882 .

Dragić, Milorad, Mitrović, Nataša Lj., Adžić, Marija, Nedeljković, Nadežda, Grković, Ivana, "Microglial- and Astrocyte-Specific Expression of Purinergic Signaling Components and Inflammatory Mediators in the Rat Hippocampus During Trimethyltin-Induced Neurodegeneration" in ASN Neuro, 13 (2021):17590914211044882,
https://doi.org/10.1177/17590914211044882 . .

TY  - CONF
AU  - Martinović, Jelena
AU  - Guševac Stojanović, Ivana
AU  - Zarić, M.
AU  - Todorović, Ana
AU  - Veljković, Filip
AU  - Pejić, Snežana
AU  - Stojanović, Zoran
AU  - Mitrović, N.
AU  - Grković, Ivana
AU  - Drakulić, Dunja
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11399
AB  - D-galactose (d-gal) is an important physiological nutrient. According to thewidely accepted aging metabolic theory d-gal at high levels can be convertedinto aldose and hydroperoxide, resulting in the overproduction of reactiveoxygen species (ROS). Increased ROS levels may subsequently cause oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis which are hallmarks of natural senescence as well as various pathological conditions. We investigated the effects of chronic oral d-gal intake (200 mg/kg and 500 mg/kg for 6 weeks) on physiological, neurological and toxicity parameters in 3 months old male Wistar rats. The obtained results indicate that body weight, food intake, serum glucose, neurological and toxicity status remained unaffected while urine proteins were significantly increased in d-gal treated rats. Although there was no effect on the general health status of the animals, our findings suggest that chronic oral d-gal administration may lead to renal dysfunction.
PB  - Belgrade : Vinča Institute of Nuclear Sciences
C3  - 7th Workshop Specific Methods for Food Safety and Quality, September 22nd, 2021, Belgrade, Serbia, 15th International Conference on Fundamental and Applied Aspects of Physical Chemistry - Physical Chemistry
T1  - Effects of chronic oral D-galactose treatment on general health status in male Wistar rats
SP  - 115
EP  - 118
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11399
ER  - 

@conference{
author = "Martinović, Jelena and Guševac Stojanović, Ivana and Zarić, M. and Todorović, Ana and Veljković, Filip and Pejić, Snežana and Stojanović, Zoran and Mitrović, N. and Grković, Ivana and Drakulić, Dunja",
year = "2021",
abstract = "D-galactose (d-gal) is an important physiological nutrient. According to thewidely accepted aging metabolic theory d-gal at high levels can be convertedinto aldose and hydroperoxide, resulting in the overproduction of reactiveoxygen species (ROS). Increased ROS levels may subsequently cause oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis which are hallmarks of natural senescence as well as various pathological conditions. We investigated the effects of chronic oral d-gal intake (200 mg/kg and 500 mg/kg for 6 weeks) on physiological, neurological and toxicity parameters in 3 months old male Wistar rats. The obtained results indicate that body weight, food intake, serum glucose, neurological and toxicity status remained unaffected while urine proteins were significantly increased in d-gal treated rats. Although there was no effect on the general health status of the animals, our findings suggest that chronic oral d-gal administration may lead to renal dysfunction.",
publisher = "Belgrade : Vinča Institute of Nuclear Sciences",
journal = "7th Workshop Specific Methods for Food Safety and Quality, September 22nd, 2021, Belgrade, Serbia, 15th International Conference on Fundamental and Applied Aspects of Physical Chemistry - Physical Chemistry",
title = "Effects of chronic oral D-galactose treatment on general health status in male Wistar rats",
pages = "115-118",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11399"
}

Martinović, J., Guševac Stojanović, I., Zarić, M., Todorović, A., Veljković, F., Pejić, S., Stojanović, Z., Mitrović, N., Grković, I.,& Drakulić, D.. (2021). Effects of chronic oral D-galactose treatment on general health status in male Wistar rats. in 7th Workshop Specific Methods for Food Safety and Quality, September 22nd, 2021, Belgrade, Serbia, 15th International Conference on Fundamental and Applied Aspects of Physical Chemistry - Physical Chemistry
Belgrade : Vinča Institute of Nuclear Sciences., 115-118.
https://hdl.handle.net/21.15107/rcub_vinar_11399

Martinović J, Guševac Stojanović I, Zarić M, Todorović A, Veljković F, Pejić S, Stojanović Z, Mitrović N, Grković I, Drakulić D. Effects of chronic oral D-galactose treatment on general health status in male Wistar rats. in 7th Workshop Specific Methods for Food Safety and Quality, September 22nd, 2021, Belgrade, Serbia, 15th International Conference on Fundamental and Applied Aspects of Physical Chemistry - Physical Chemistry. 2021;:115-118.
https://hdl.handle.net/21.15107/rcub_vinar_11399 .

Martinović, Jelena, Guševac Stojanović, Ivana, Zarić, M., Todorović, Ana, Veljković, Filip, Pejić, Snežana, Stojanović, Zoran, Mitrović, N., Grković, Ivana, Drakulić, Dunja, "Effects of chronic oral D-galactose treatment on general health status in male Wistar rats" in 7th Workshop Specific Methods for Food Safety and Quality, September 22nd, 2021, Belgrade, Serbia, 15th International Conference on Fundamental and Applied Aspects of Physical Chemistry - Physical Chemistry (2021):115-118,
https://hdl.handle.net/21.15107/rcub_vinar_11399 .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Zeljković, Milica
AU  - Stevanović, Ivana
AU  - Adžić, Marija
AU  - Stekić, Anđela
AU  - Mihajlović, Katarina
AU  - Grković, Ivana
AU  - Ilić, Nela
AU  - Ilić, Tihomir V.
AU  - Nedeljković, Nadežda
AU  - Ninković, Milica
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10082
AB  - Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model—experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A2AR/A1R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1β and NF- κB-ir and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.
T2  - Brain Sciences
T2  - Brain Sciences
T1  - Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis
VL  - 11
IS  - 6
SP  - 736
DO  - 10.3390/brainsci11060736
ER  - 

@article{
author = "Dragić, Milorad and Zeljković, Milica and Stevanović, Ivana and Adžić, Marija and Stekić, Anđela and Mihajlović, Katarina and Grković, Ivana and Ilić, Nela and Ilić, Tihomir V. and Nedeljković, Nadežda and Ninković, Milica",
year = "2021",
abstract = "Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model—experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A2AR/A1R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1β and NF- κB-ir and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.",
journal = "Brain Sciences, Brain Sciences",
title = "Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis",
volume = "11",
number = "6",
pages = "736",
doi = "10.3390/brainsci11060736"
}

Dragić, M., Zeljković, M., Stevanović, I., Adžić, M., Stekić, A., Mihajlović, K., Grković, I., Ilić, N., Ilić, T. V., Nedeljković, N.,& Ninković, M.. (2021). Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis. in Brain Sciences, 11(6), 736.
https://doi.org/10.3390/brainsci11060736

Dragić M, Zeljković M, Stevanović I, Adžić M, Stekić A, Mihajlović K, Grković I, Ilić N, Ilić TV, Nedeljković N, Ninković M. Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis. in Brain Sciences. 2021;11(6):736.
doi:10.3390/brainsci11060736 .

Dragić, Milorad, Zeljković, Milica, Stevanović, Ivana, Adžić, Marija, Stekić, Anđela, Mihajlović, Katarina, Grković, Ivana, Ilić, Nela, Ilić, Tihomir V., Nedeljković, Nadežda, Ninković, Milica, "Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis" in Brain Sciences, 11, no. 6 (2021):736,
https://doi.org/10.3390/brainsci11060736 . .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Milićević, Katarina
AU  - Adžić, Marija
AU  - Stevanović, Ivana
AU  - Ninković, Milica
AU  - Grković, Ivana
AU  - Anđus, Pavle
AU  - Nedeljković, Nadežda
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9174
AB  - Astrocytes are the first responders to noxious stimuli by undergoing cellular and functional transition referred as reactive gliosis. Every acute or chronic disorder is accompanied by reactive gliosis, which could be categorized as detrimental (A1) of beneficial (A2) for nervous tissue. Another signature of pathological astrocyte activation is disturbed Ca2+ homeostasis, a common denominator of neurodegenerative diseases. Deregulation of Ca+ signaling further contributes to production of pro-inflammatory cytokines and reactive oxygen species. Trimethyltin (TMT) intoxication is a widely used model of hippocampal degeneration, sharing behavioral and molecular hallmarks of Alzheimer’s disease (AD), thus representing a useful model of AD-like pathology. However, the role of astrocyte in the etiopathology of TMT-induced degeneration as well as in AD is not fully understood. In an effort to elucidate the role of astrocytes in such pathological processes, we examined in vitro effects of TMT on primary cortical astrocytes. The application of a range of TMT concentrations (5, 10, 50, and 100 μM) revealed changes in [Ca2+]i in a dose-dependent manner. Specifically, TMT-induced Ca2+ transients were due to L-type voltage-gated calcium channels (VGCC). Additionally, TMT induced mitochondrial depolarization independent of extracellular Ca2+ and disturbed antioxidative defense of astrocyte in several time points (4, 6, and 24 h) after 10 μM TMT intoxication, inducing oxidative and nitrosative stress. Chronic exposure (24 h) to 10 μM TMT induced strong upregulation of main pro-inflammatory factors, components of signaling pathways in astrocyte activation, A1 markers, and VGCC. Taken together, our results provide an insight into cellular and molecular events of astrocyte activation in chronic neuroinflammation. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
T2  - Molecular Neurobiology
T1  - Trimethyltin Increases Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels and Promotes Inflammatory Phenotype in Rat Astrocytes In Vitro
VL  - 58
IS  - 4
SP  - 1792
EP  - 1805
DO  - 10.1007/s12035-020-02273-x
ER  - 

@article{
author = "Dragić, Milorad and Milićević, Katarina and Adžić, Marija and Stevanović, Ivana and Ninković, Milica and Grković, Ivana and Anđus, Pavle and Nedeljković, Nadežda",
year = "2021",
abstract = "Astrocytes are the first responders to noxious stimuli by undergoing cellular and functional transition referred as reactive gliosis. Every acute or chronic disorder is accompanied by reactive gliosis, which could be categorized as detrimental (A1) of beneficial (A2) for nervous tissue. Another signature of pathological astrocyte activation is disturbed Ca2+ homeostasis, a common denominator of neurodegenerative diseases. Deregulation of Ca+ signaling further contributes to production of pro-inflammatory cytokines and reactive oxygen species. Trimethyltin (TMT) intoxication is a widely used model of hippocampal degeneration, sharing behavioral and molecular hallmarks of Alzheimer’s disease (AD), thus representing a useful model of AD-like pathology. However, the role of astrocyte in the etiopathology of TMT-induced degeneration as well as in AD is not fully understood. In an effort to elucidate the role of astrocytes in such pathological processes, we examined in vitro effects of TMT on primary cortical astrocytes. The application of a range of TMT concentrations (5, 10, 50, and 100 μM) revealed changes in [Ca2+]i in a dose-dependent manner. Specifically, TMT-induced Ca2+ transients were due to L-type voltage-gated calcium channels (VGCC). Additionally, TMT induced mitochondrial depolarization independent of extracellular Ca2+ and disturbed antioxidative defense of astrocyte in several time points (4, 6, and 24 h) after 10 μM TMT intoxication, inducing oxidative and nitrosative stress. Chronic exposure (24 h) to 10 μM TMT induced strong upregulation of main pro-inflammatory factors, components of signaling pathways in astrocyte activation, A1 markers, and VGCC. Taken together, our results provide an insight into cellular and molecular events of astrocyte activation in chronic neuroinflammation. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.",
journal = "Molecular Neurobiology",
title = "Trimethyltin Increases Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels and Promotes Inflammatory Phenotype in Rat Astrocytes In Vitro",
volume = "58",
number = "4",
pages = "1792-1805",
doi = "10.1007/s12035-020-02273-x"
}

Dragić, M., Milićević, K., Adžić, M., Stevanović, I., Ninković, M., Grković, I., Anđus, P.,& Nedeljković, N.. (2021). Trimethyltin Increases Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels and Promotes Inflammatory Phenotype in Rat Astrocytes In Vitro. in Molecular Neurobiology, 58(4), 1792-1805.
https://doi.org/10.1007/s12035-020-02273-x

Dragić M, Milićević K, Adžić M, Stevanović I, Ninković M, Grković I, Anđus P, Nedeljković N. Trimethyltin Increases Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels and Promotes Inflammatory Phenotype in Rat Astrocytes In Vitro. in Molecular Neurobiology. 2021;58(4):1792-1805.
doi:10.1007/s12035-020-02273-x .

Dragić, Milorad, Milićević, Katarina, Adžić, Marija, Stevanović, Ivana, Ninković, Milica, Grković, Ivana, Anđus, Pavle, Nedeljković, Nadežda, "Trimethyltin Increases Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels and Promotes Inflammatory Phenotype in Rat Astrocytes In Vitro" in Molecular Neurobiology, 58, no. 4 (2021):1792-1805,
https://doi.org/10.1007/s12035-020-02273-x . .

TY  - CHAP
AU  - Grković, Ivana
AU  - Mitrović, Nataša Lj.
AU  - Dragić, Milorad
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10095
AB  - Extracellular purine nucleotides, such as adenosine 5′-triphosphate (ATP), are important modulators of hippocampal function and plasticity. In the extracellular space, ATP is inherently short-lived molecule, which undergoes rapid enzymatic degradation to adenosine by ectonucleotidases. Given that ectonucleotidases have distinct and overlapping distribution in the hippocampus, and as ovarian hormones participate in a formation, maturation, and a refinement of synaptic contacts, both during development and in adulthood, the present chapter summarizes known data about spatial distribution of selected ecto-enzymes and estradiol-induced effects on ectonucleotidases in the rat hippocampus.
T2  - Vitamins and Hormones
T1  - Ectonucleotidases in the hippocampus: Spatial distribution and expression after ovariectomy and estradiol replacement
VL  - 118
SP  - 199
EP  - 221
DO  - 10.1016/bs.vh.2021.11.005
ER  - 

@inbook{
author = "Grković, Ivana and Mitrović, Nataša Lj. and Dragić, Milorad",
year = "2021",
abstract = "Extracellular purine nucleotides, such as adenosine 5′-triphosphate (ATP), are important modulators of hippocampal function and plasticity. In the extracellular space, ATP is inherently short-lived molecule, which undergoes rapid enzymatic degradation to adenosine by ectonucleotidases. Given that ectonucleotidases have distinct and overlapping distribution in the hippocampus, and as ovarian hormones participate in a formation, maturation, and a refinement of synaptic contacts, both during development and in adulthood, the present chapter summarizes known data about spatial distribution of selected ecto-enzymes and estradiol-induced effects on ectonucleotidases in the rat hippocampus.",
journal = "Vitamins and Hormones",
booktitle = "Ectonucleotidases in the hippocampus: Spatial distribution and expression after ovariectomy and estradiol replacement",
volume = "118",
pages = "199-221",
doi = "10.1016/bs.vh.2021.11.005"
}

Grković, I., Mitrović, N. Lj.,& Dragić, M.. (2021). Ectonucleotidases in the hippocampus: Spatial distribution and expression after ovariectomy and estradiol replacement. in Vitamins and Hormones, 118, 199-221.
https://doi.org/10.1016/bs.vh.2021.11.005

Grković I, Mitrović NL, Dragić M. Ectonucleotidases in the hippocampus: Spatial distribution and expression after ovariectomy and estradiol replacement. in Vitamins and Hormones. 2021;118:199-221.
doi:10.1016/bs.vh.2021.11.005 .

Grković, Ivana, Mitrović, Nataša Lj., Dragić, Milorad, "Ectonucleotidases in the hippocampus: Spatial distribution and expression after ovariectomy and estradiol replacement" in Vitamins and Hormones, 118 (2021):199-221,
https://doi.org/10.1016/bs.vh.2021.11.005 . .

TY  - JOUR
AU  - Stanojlović, Miloš R.
AU  - Guševac Stojanović, Ivana
AU  - Zarić, Marina
AU  - Martinović, Jelena
AU  - Mitrović, Nataša Lj.
AU  - Grković, Ivana
AU  - Drakulić, Dunja R.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8742
AB  - Sustained activation of pro-apoptotic signaling due to a sudden and prolonged disturbance of cerebral blood circulation governs the neurodegenerative processes in prefrontal cortex (PFC) of rats whose common carotid arteries are permanently occluded. The adequate neuroprotective therapy should minimize the activation of toxicity pathways and increase the activity of endogenous protective mechanisms. Several neuroprotectants have been proposed, including progesterone (P4). However, the underlying mechanism of its action in PFC following permanent bilateral occlusion of common carotid arteries is not completely investigated. We, thus herein, tested the impact of post-ischemic P4 treatment (1.7 mg/kg for seven consecutive days) on previously reported aberrant neuronal morphology and amount of DNA fragmentation, as well as the expression of progesterone receptors along with the key elements of Akt/Erk/eNOS signal transduction pathway (Bax, Bcl-2, cytochrome C, caspase 3, PARP, and the level of nitric oxide). The obtained results indicate that potential amelioration of histological changes in PFC might be associated with the absence of activation of Bax/caspase 3 signaling cascade and the decline of DNA fragmentation. The study also provides the evidence that P4 treatment in repeated regiment of administration might be effective in neuronal protection against ischemic insult due to re-establishment of the compromised action of Akt/Erk/eNOS-mediated signaling pathway and the upregulation of progesterone receptors. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
T2  - Cellular and Molecular Neurobiology
T1  - Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS
VL  - 40
IS  - 5
SP  - 829
EP  - 843
DO  - 10.1007/s10571-019-00777-2
ER  - 

@article{
author = "Stanojlović, Miloš R. and Guševac Stojanović, Ivana and Zarić, Marina and Martinović, Jelena and Mitrović, Nataša Lj. and Grković, Ivana and Drakulić, Dunja R.",
year = "2020",
abstract = "Sustained activation of pro-apoptotic signaling due to a sudden and prolonged disturbance of cerebral blood circulation governs the neurodegenerative processes in prefrontal cortex (PFC) of rats whose common carotid arteries are permanently occluded. The adequate neuroprotective therapy should minimize the activation of toxicity pathways and increase the activity of endogenous protective mechanisms. Several neuroprotectants have been proposed, including progesterone (P4). However, the underlying mechanism of its action in PFC following permanent bilateral occlusion of common carotid arteries is not completely investigated. We, thus herein, tested the impact of post-ischemic P4 treatment (1.7 mg/kg for seven consecutive days) on previously reported aberrant neuronal morphology and amount of DNA fragmentation, as well as the expression of progesterone receptors along with the key elements of Akt/Erk/eNOS signal transduction pathway (Bax, Bcl-2, cytochrome C, caspase 3, PARP, and the level of nitric oxide). The obtained results indicate that potential amelioration of histological changes in PFC might be associated with the absence of activation of Bax/caspase 3 signaling cascade and the decline of DNA fragmentation. The study also provides the evidence that P4 treatment in repeated regiment of administration might be effective in neuronal protection against ischemic insult due to re-establishment of the compromised action of Akt/Erk/eNOS-mediated signaling pathway and the upregulation of progesterone receptors. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.",
journal = "Cellular and Molecular Neurobiology",
title = "Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS",
volume = "40",
number = "5",
pages = "829-843",
doi = "10.1007/s10571-019-00777-2"
}

Stanojlović, M. R., Guševac Stojanović, I., Zarić, M., Martinović, J., Mitrović, N. Lj., Grković, I.,& Drakulić, D. R.. (2020). Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS. in Cellular and Molecular Neurobiology, 40(5), 829-843.
https://doi.org/10.1007/s10571-019-00777-2

Stanojlović MR, Guševac Stojanović I, Zarić M, Martinović J, Mitrović NL, Grković I, Drakulić DR. Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS. in Cellular and Molecular Neurobiology. 2020;40(5):829-843.
doi:10.1007/s10571-019-00777-2 .

Stanojlović, Miloš R., Guševac Stojanović, Ivana, Zarić, Marina, Martinović, Jelena, Mitrović, Nataša Lj., Grković, Ivana, Drakulić, Dunja R., "Progesterone Protects Prefrontal Cortex in Rat Model of Permanent Bilateral Common Carotid Occlusion via Progesterone Receptors and Akt/Erk/eNOS" in Cellular and Molecular Neurobiology, 40, no. 5 (2020):829-843,
https://doi.org/10.1007/s10571-019-00777-2 . .

TY  - CHAP
AU  - Grković, Ivana
AU  - Mitrović, Nataša Lj.
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9056
AB  - 17β-Estradiol (E2) is a potent steroid hormone of both gonadal and neuronal origin that exerts profound effects on neuroplasticity in several brain regions. Dendritic spine and synapse formation and rearrangements are modulated and mediated by estrogens. In this chapter, we highlighted the essential background concerning the effects of E2 on synaptic rearrangements accompanied by synaptic plasticity in E2-sensitive brain regions that mediate learning and memory, i.e., cortex and hippocampus. We also address details of the molecular mechanisms underlying E2 regulation of spine dynamics. The proposed models of action of E2 overlaps with that for well-established synaptic modulators, such as adenosine. Thus, the possible synergistic effects of those two molecules in respect to synaptic rearrangement and plasticity were presented.
T2  - Vitamins and Hormones
T1  - Estradiol induces synaptic rearrangements
VL  - 114
SP  - 233
EP  - 256
DO  - 10.1016/bs.vh.2020.04.006
ER  - 

@inbook{
author = "Grković, Ivana and Mitrović, Nataša Lj.",
year = "2020",
abstract = "17β-Estradiol (E2) is a potent steroid hormone of both gonadal and neuronal origin that exerts profound effects on neuroplasticity in several brain regions. Dendritic spine and synapse formation and rearrangements are modulated and mediated by estrogens. In this chapter, we highlighted the essential background concerning the effects of E2 on synaptic rearrangements accompanied by synaptic plasticity in E2-sensitive brain regions that mediate learning and memory, i.e., cortex and hippocampus. We also address details of the molecular mechanisms underlying E2 regulation of spine dynamics. The proposed models of action of E2 overlaps with that for well-established synaptic modulators, such as adenosine. Thus, the possible synergistic effects of those two molecules in respect to synaptic rearrangement and plasticity were presented.",
journal = "Vitamins and Hormones",
booktitle = "Estradiol induces synaptic rearrangements",
volume = "114",
pages = "233-256",
doi = "10.1016/bs.vh.2020.04.006"
}

Grković, I.,& Mitrović, N. Lj.. (2020). Estradiol induces synaptic rearrangements. in Vitamins and Hormones, 114, 233-256.
https://doi.org/10.1016/bs.vh.2020.04.006

Grković I, Mitrović NL. Estradiol induces synaptic rearrangements. in Vitamins and Hormones. 2020;114:233-256.
doi:10.1016/bs.vh.2020.04.006 .

Grković, Ivana, Mitrović, Nataša Lj., "Estradiol induces synaptic rearrangements" in Vitamins and Hormones, 114 (2020):233-256,
https://doi.org/10.1016/bs.vh.2020.04.006 . .

TY  - JOUR
AU  - Grković, Ivana
AU  - Drakulić, Dunja R.
AU  - Martinović, Jelena
AU  - Mitrović, Nataša Lj.
PY  - 2019
UR  - http://www.eurekaselect.com/node/152565/article
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/7758
AB  - Extracellular adenine nucleotides and nucleosides, such as ATP and adenosine, are among the most recently identified and least investigated diffusible signaling factors that contribute to the structural and functional remodeling of the brain, both during embryonic and postnatal development. Their levels in the extracellular milieu are tightly controlled by various ectonucleotidases: ectonucleotide pyrophosphatase/phosphodiesterases (E-NPP), alkaline phosphatases (AP), ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eN). During central nervous system development and in adulthood all ectonucleotidases have diverse expression pattern, cell specific localization and function. Formation, maturation, and refinement of synaptic contacts are influenced by neurotransmitters and neuromodulators, and control of extracellular adenine nucleotide levels by ectonucleotidases are important for understanding the role of purinergic signaling in developing tissues and potential targets in developmental disorders such as autism.
T2  - Current Neuropharmacology
T1  - Role of Ectonucleotidases in the Synapse Formation During Brain Development: Physiological and Pathological Implications
VL  - 17
IS  - 1
SP  - 84
EP  - 98
DO  - 10.2174/1570159X15666170518151541
ER  - 

@article{
author = "Grković, Ivana and Drakulić, Dunja R. and Martinović, Jelena and Mitrović, Nataša Lj.",
year = "2019",
abstract = "Extracellular adenine nucleotides and nucleosides, such as ATP and adenosine, are among the most recently identified and least investigated diffusible signaling factors that contribute to the structural and functional remodeling of the brain, both during embryonic and postnatal development. Their levels in the extracellular milieu are tightly controlled by various ectonucleotidases: ectonucleotide pyrophosphatase/phosphodiesterases (E-NPP), alkaline phosphatases (AP), ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eN). During central nervous system development and in adulthood all ectonucleotidases have diverse expression pattern, cell specific localization and function. Formation, maturation, and refinement of synaptic contacts are influenced by neurotransmitters and neuromodulators, and control of extracellular adenine nucleotide levels by ectonucleotidases are important for understanding the role of purinergic signaling in developing tissues and potential targets in developmental disorders such as autism.",
journal = "Current Neuropharmacology",
title = "Role of Ectonucleotidases in the Synapse Formation During Brain Development: Physiological and Pathological Implications",
volume = "17",
number = "1",
pages = "84-98",
doi = "10.2174/1570159X15666170518151541"
}

Grković, I., Drakulić, D. R., Martinović, J.,& Mitrović, N. Lj.. (2019). Role of Ectonucleotidases in the Synapse Formation During Brain Development: Physiological and Pathological Implications. in Current Neuropharmacology, 17(1), 84-98.
https://doi.org/10.2174/1570159X15666170518151541

Grković I, Drakulić DR, Martinović J, Mitrović NL. Role of Ectonucleotidases in the Synapse Formation During Brain Development: Physiological and Pathological Implications. in Current Neuropharmacology. 2019;17(1):84-98.
doi:10.2174/1570159X15666170518151541 .

Grković, Ivana, Drakulić, Dunja R., Martinović, Jelena, Mitrović, Nataša Lj., "Role of Ectonucleotidases in the Synapse Formation During Brain Development: Physiological and Pathological Implications" in Current Neuropharmacology, 17, no. 1 (2019):84-98,
https://doi.org/10.2174/1570159X15666170518151541 . .

TY  - JOUR
AU  - Zarić, Marina
AU  - Drakulić, Dunja R.
AU  - Dragić, Milorad
AU  - Guševac Stojanović, Ivana
AU  - Mitrović, Nataša Lj.
AU  - Grković, Ivana
AU  - Martinović, Jelena
PY  - 2019
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0306452219303227
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8203
AB  - Transient ischemic attack (TIA) represents brief neurological dysfunction of vascular origin without detectable infarction. Despite major clinical relevance characterization of post-TIA molecular changes using appropriate experimental model is lacking and no therapeutic agent has been established yet. Neurosteroid dehydroepiandrosterone (DHEA) arose as one of the candidates for cerebral ischemia treatment but its effects on TIA-like condition remain unknown. Seeking an animal model applicable for investigation of molecular alterations in mild ischemic conditions such as TIA, 15-min bilateral common carotid artery occlusion with 24-h reperfusion was performed to induce ischemia/ reperfusion (I/R) injury in adult male Wistar rats. Additionally, effects of 4-h post-operative DHEA treatment (20 mg/kg) were investigated in physiological and I/R conditions in hippocampus (HIP) and prefrontal cortex (PFC). The study revealed absence of sensorimotor deficits, cerebral infarcts and neurodegeneration along with preserved HIP and PFC overall neuronal morphology and unaltered malondialdehyde and reduced glutathione level following I/R and/or DHEA treatment. I/R induced nitric oxide burst in HIP and PFC was accompanied with increased neuronal nitric oxide synthase protein level exclusively in HIP. DHEA had no effects in physiological conditions, while increase of Bax/Bcl2 ratio and dissipation of mitochondrial membrane potential in treated I/R group suggested DHEA-mediated exacerbation of post-ischemic changes that might lead to pro-apoptotic events in HIP. Interestingly, DHEA restored I/R-induced NO to the control level in PFC. Obtained results indicated that I/R may serve as an appropriate model for investigation of molecular changes and treatment outcome following mild ischemic conditions such as TIA. © 2019 Elsevier Ltd
T2  - Neuroscience
T1  - Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack
VL  - 410
SP  - 128
EP  - 139
DO  - 10.1016/j.neuroscience.2019.05.006
ER  - 

@article{
author = "Zarić, Marina and Drakulić, Dunja R. and Dragić, Milorad and Guševac Stojanović, Ivana and Mitrović, Nataša Lj. and Grković, Ivana and Martinović, Jelena",
year = "2019",
abstract = "Transient ischemic attack (TIA) represents brief neurological dysfunction of vascular origin without detectable infarction. Despite major clinical relevance characterization of post-TIA molecular changes using appropriate experimental model is lacking and no therapeutic agent has been established yet. Neurosteroid dehydroepiandrosterone (DHEA) arose as one of the candidates for cerebral ischemia treatment but its effects on TIA-like condition remain unknown. Seeking an animal model applicable for investigation of molecular alterations in mild ischemic conditions such as TIA, 15-min bilateral common carotid artery occlusion with 24-h reperfusion was performed to induce ischemia/ reperfusion (I/R) injury in adult male Wistar rats. Additionally, effects of 4-h post-operative DHEA treatment (20 mg/kg) were investigated in physiological and I/R conditions in hippocampus (HIP) and prefrontal cortex (PFC). The study revealed absence of sensorimotor deficits, cerebral infarcts and neurodegeneration along with preserved HIP and PFC overall neuronal morphology and unaltered malondialdehyde and reduced glutathione level following I/R and/or DHEA treatment. I/R induced nitric oxide burst in HIP and PFC was accompanied with increased neuronal nitric oxide synthase protein level exclusively in HIP. DHEA had no effects in physiological conditions, while increase of Bax/Bcl2 ratio and dissipation of mitochondrial membrane potential in treated I/R group suggested DHEA-mediated exacerbation of post-ischemic changes that might lead to pro-apoptotic events in HIP. Interestingly, DHEA restored I/R-induced NO to the control level in PFC. Obtained results indicated that I/R may serve as an appropriate model for investigation of molecular changes and treatment outcome following mild ischemic conditions such as TIA. © 2019 Elsevier Ltd",
journal = "Neuroscience",
title = "Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack",
volume = "410",
pages = "128-139",
doi = "10.1016/j.neuroscience.2019.05.006"
}

Zarić, M., Drakulić, D. R., Dragić, M., Guševac Stojanović, I., Mitrović, N. Lj., Grković, I.,& Martinović, J.. (2019). Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack. in Neuroscience, 410, 128-139.
https://doi.org/10.1016/j.neuroscience.2019.05.006

Zarić M, Drakulić DR, Dragić M, Guševac Stojanović I, Mitrović NL, Grković I, Martinović J. Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack. in Neuroscience. 2019;410:128-139.
doi:10.1016/j.neuroscience.2019.05.006 .

Zarić, Marina, Drakulić, Dunja R., Dragić, Milorad, Guševac Stojanović, Ivana, Mitrović, Nataša Lj., Grković, Ivana, Martinović, Jelena, "Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack" in Neuroscience, 410 (2019):128-139,
https://doi.org/10.1016/j.neuroscience.2019.05.006 . .

TY  - JOUR
AU  - Grković, Ivana
AU  - Mitrović, Nataša Lj.
AU  - Dragić, Milorad
AU  - Adžić, Marija
AU  - Drakulić, Dunja R.
AU  - Nedeljković, Nadežda
PY  - 2019
UR  - http://link.springer.com/10.1007/s12035-018-1217-3
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8102
AB  - Purinergic signaling is the main synaptic and non-synaptic signaling system in brain. ATP acts as a fast excitatory transmitter, while adenosine sets a global inhibitory tone within hippocampal neuronal networks. ATP and adenosine are interconnected by ectonucleotidase enzymes, which convert ATP to adenosine. Existing data point to the converging roles of ovarian steroids and purinergic signaling in synapse formation and refinement and synapse activity in the hippocampus. Therefore, in the present study, we have used enzyme histochemistry and expression analysis to obtain data on spatial distribution and expression of ecto-enzymes NTPDase1, NTPDase2, and ecto-5-nucleotidase (eN) after removal of ovaries (OVX) and estradiol replacement (E2) in female rat hippocampus. The results show that target ectonucleotidases are predominantly localized in synapse-rich hippocampal layers. The most represented NTPDase in the hippocampal tissue is NTPDase2, being at the same time the mostly affected ectonucleotidase by OVX and E2. Specifically, OVX decreases the expression of NTPDase2 and eN, whereas E2 restores their expression to control level. Impact of OVX and E2 on ectonucleotidase expression was also examined in purified synaptosome (SYN) and gliosome (GLIO) fractions. Data reveal that SYN expresses NTPDase1 and NTPDase2, both of which are reduced following OVX and restored with E2. GLIO exhibits NTPDase2-mediated ATP hydrolysis, which falls in OVX, and recovers by E2. These changes in the activity occur without parallel changes in NTPDase2-protein abundance. The same holds for eN. The lack of correlation between NTPDase2 and eN activities and their respective protein abundances suggest a non-genomic mode of E2 action, which is studied further in primary astrocyte culture. Since ovarian steroids shape hippocampal synaptic networks and regulate ectonucleotidase activities, it is possible that cognitive deficits seen after ovary removal may arise from the loss of E2 modulatory actions on ectonucleotidase expression in the hippocampus.
T2  - Molecular Neurobiology
T2  - Molecular Neurobiology
T1  - Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement
VL  - 56
IS  - 3
SP  - 1933
EP  - 1945
DO  - 10.1007/s12035-018-1217-3
ER  - 

@article{
author = "Grković, Ivana and Mitrović, Nataša Lj. and Dragić, Milorad and Adžić, Marija and Drakulić, Dunja R. and Nedeljković, Nadežda",
year = "2019",
abstract = "Purinergic signaling is the main synaptic and non-synaptic signaling system in brain. ATP acts as a fast excitatory transmitter, while adenosine sets a global inhibitory tone within hippocampal neuronal networks. ATP and adenosine are interconnected by ectonucleotidase enzymes, which convert ATP to adenosine. Existing data point to the converging roles of ovarian steroids and purinergic signaling in synapse formation and refinement and synapse activity in the hippocampus. Therefore, in the present study, we have used enzyme histochemistry and expression analysis to obtain data on spatial distribution and expression of ecto-enzymes NTPDase1, NTPDase2, and ecto-5-nucleotidase (eN) after removal of ovaries (OVX) and estradiol replacement (E2) in female rat hippocampus. The results show that target ectonucleotidases are predominantly localized in synapse-rich hippocampal layers. The most represented NTPDase in the hippocampal tissue is NTPDase2, being at the same time the mostly affected ectonucleotidase by OVX and E2. Specifically, OVX decreases the expression of NTPDase2 and eN, whereas E2 restores their expression to control level. Impact of OVX and E2 on ectonucleotidase expression was also examined in purified synaptosome (SYN) and gliosome (GLIO) fractions. Data reveal that SYN expresses NTPDase1 and NTPDase2, both of which are reduced following OVX and restored with E2. GLIO exhibits NTPDase2-mediated ATP hydrolysis, which falls in OVX, and recovers by E2. These changes in the activity occur without parallel changes in NTPDase2-protein abundance. The same holds for eN. The lack of correlation between NTPDase2 and eN activities and their respective protein abundances suggest a non-genomic mode of E2 action, which is studied further in primary astrocyte culture. Since ovarian steroids shape hippocampal synaptic networks and regulate ectonucleotidase activities, it is possible that cognitive deficits seen after ovary removal may arise from the loss of E2 modulatory actions on ectonucleotidase expression in the hippocampus.",
journal = "Molecular Neurobiology, Molecular Neurobiology",
title = "Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement",
volume = "56",
number = "3",
pages = "1933-1945",
doi = "10.1007/s12035-018-1217-3"
}

Grković, I., Mitrović, N. Lj., Dragić, M., Adžić, M., Drakulić, D. R.,& Nedeljković, N.. (2019). Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement. in Molecular Neurobiology, 56(3), 1933-1945.
https://doi.org/10.1007/s12035-018-1217-3

Grković I, Mitrović NL, Dragić M, Adžić M, Drakulić DR, Nedeljković N. Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement. in Molecular Neurobiology. 2019;56(3):1933-1945.
doi:10.1007/s12035-018-1217-3 .

Grković, Ivana, Mitrović, Nataša Lj., Dragić, Milorad, Adžić, Marija, Drakulić, Dunja R., Nedeljković, Nadežda, "Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement" in Molecular Neurobiology, 56, no. 3 (2019):1933-1945,
https://doi.org/10.1007/s12035-018-1217-3 . .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Zarić, Marina
AU  - Mitrović, Nataša Lj.
AU  - Nedeljković, Nadežda
AU  - Grković, Ivana
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8489
AB  - Enzyme histochemistry is a valuable histological method which provides a connection between morphology, activity, and spatial localization of investigated enzymes. Even though the method relies purely on arbitrary evaluations performed by the human eye, it is still wildly accepted and used in histo(patho)logy. Texture analysis emerged as an excellent tool for image quantification of subtle differences reflected in both spatial discrepancies and gray level values of pixels. The current study of texture analysis utilizes the gray-level co-occurrence matrix as a method for quantification of differences between ecto-5′-nucleotidase activities in healthy hippocampal tissue and tissue with marked neurodegeneration. We used the angular second moment, contrast (CON), correlation, inverse difference moment (INV), and entropy for texture analysis and receiver operating characteristic analysis with immunoblot and qualitative assessment of enzyme histochemistry as a validation. Our results strongly argue that co-occurrence matrix analysis could be used for the determination of fine differences in the enzyme activities with the possibility to ascribe those differences to regions or specific cell types. In addition, it emerged that INV and CON are especially useful parameters for this type of enzyme histochemistry analysis. We concluded that texture analysis is a reliable method for quantification of this descriptive technique, thus removing biases and adding it a quantitative dimension.
T2  - Microscopy and Microanalysis
T1  - Application of Gray Level Co-Occurrence Matrix Analysis as a New Method for Enzyme Histochemistry Quantification
VL  - 25
IS  - 3
SP  - 690
EP  - 698
DO  - 10.1017/S1431927618016306
ER  - 

@article{
author = "Dragić, Milorad and Zarić, Marina and Mitrović, Nataša Lj. and Nedeljković, Nadežda and Grković, Ivana",
year = "2019",
abstract = "Enzyme histochemistry is a valuable histological method which provides a connection between morphology, activity, and spatial localization of investigated enzymes. Even though the method relies purely on arbitrary evaluations performed by the human eye, it is still wildly accepted and used in histo(patho)logy. Texture analysis emerged as an excellent tool for image quantification of subtle differences reflected in both spatial discrepancies and gray level values of pixels. The current study of texture analysis utilizes the gray-level co-occurrence matrix as a method for quantification of differences between ecto-5′-nucleotidase activities in healthy hippocampal tissue and tissue with marked neurodegeneration. We used the angular second moment, contrast (CON), correlation, inverse difference moment (INV), and entropy for texture analysis and receiver operating characteristic analysis with immunoblot and qualitative assessment of enzyme histochemistry as a validation. Our results strongly argue that co-occurrence matrix analysis could be used for the determination of fine differences in the enzyme activities with the possibility to ascribe those differences to regions or specific cell types. In addition, it emerged that INV and CON are especially useful parameters for this type of enzyme histochemistry analysis. We concluded that texture analysis is a reliable method for quantification of this descriptive technique, thus removing biases and adding it a quantitative dimension.",
journal = "Microscopy and Microanalysis",
title = "Application of Gray Level Co-Occurrence Matrix Analysis as a New Method for Enzyme Histochemistry Quantification",
volume = "25",
number = "3",
pages = "690-698",
doi = "10.1017/S1431927618016306"
}

Dragić, M., Zarić, M., Mitrović, N. Lj., Nedeljković, N.,& Grković, I.. (2019). Application of Gray Level Co-Occurrence Matrix Analysis as a New Method for Enzyme Histochemistry Quantification. in Microscopy and Microanalysis, 25(3), 690-698.
https://doi.org/10.1017/S1431927618016306

Dragić M, Zarić M, Mitrović NL, Nedeljković N, Grković I. Application of Gray Level Co-Occurrence Matrix Analysis as a New Method for Enzyme Histochemistry Quantification. in Microscopy and Microanalysis. 2019;25(3):690-698.
doi:10.1017/S1431927618016306 .

Dragić, Milorad, Zarić, Marina, Mitrović, Nataša Lj., Nedeljković, Nadežda, Grković, Ivana, "Application of Gray Level Co-Occurrence Matrix Analysis as a New Method for Enzyme Histochemistry Quantification" in Microscopy and Microanalysis, 25, no. 3 (2019):690-698,
https://doi.org/10.1017/S1431927618016306 . .

TY  - JOUR
AU  - Mitrović, Nataša Lj.
AU  - Dragić, Milorad
AU  - Zarić, Marina
AU  - Drakulić, Dunja R.
AU  - Nedeljković, Nadežda
AU  - Grković, Ivana
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8497
AB  - Extracellular adenine nucleotides and nucleosides, such as adenosine-5'-triphosphate (ATP) and adenosine, are among least investigated signaling factors that participate in 17β-estradiol (E2)-mediated synaptic rearrangements in rodent hippocampus. Their levels in the extrasynaptic space are tightly controlled by ecto-nucleoside triphosphate diphosphohydrolases1-3 (NTPDase1-3)/ecto-5'-nucleotidase (eN) enzyme chain. Therefore, the aim of the present study was to get closer insight in the E2-induced decrease in NTPDase and eN activity in the hippocampal synaptic compartment of male rats and to identify estradiol receptors (ERs i.e. ERα, ERβ or GPER1) responsible for the observed effects of E2. In this study we show indiscriminate participation of estradiol receptor α (ERα), -β (ERβ) and G- protein coupled estrogen receptor 1 (GPER1) in the mediation of E2 actions in hippocampal synaptosomes of male rats. Synaptic NTPDase1-3 activities are modulated only through activation of ERβ, while activation of ERα, -β and/or non-classical GPER1 decreases synaptic eN activity. Since both ATP and adenosine function as neuromodulators in the hippocampal networks, influencing its function, profound knowledge of mechanisms by which ectonucleotidases are regulated/modulated is of great importance. © 2019 Elsevier B.V.
T2  - Neuroscience Letters
T1  - Estrogen receptors modulate ectonucleotidases activity in hippocampal synaptosomes of male rats
VL  - 712
SP  - 134474
DO  - 10.1016/j.neulet.2019.134474
ER  - 

@article{
author = "Mitrović, Nataša Lj. and Dragić, Milorad and Zarić, Marina and Drakulić, Dunja R. and Nedeljković, Nadežda and Grković, Ivana",
year = "2019",
abstract = "Extracellular adenine nucleotides and nucleosides, such as adenosine-5'-triphosphate (ATP) and adenosine, are among least investigated signaling factors that participate in 17β-estradiol (E2)-mediated synaptic rearrangements in rodent hippocampus. Their levels in the extrasynaptic space are tightly controlled by ecto-nucleoside triphosphate diphosphohydrolases1-3 (NTPDase1-3)/ecto-5'-nucleotidase (eN) enzyme chain. Therefore, the aim of the present study was to get closer insight in the E2-induced decrease in NTPDase and eN activity in the hippocampal synaptic compartment of male rats and to identify estradiol receptors (ERs i.e. ERα, ERβ or GPER1) responsible for the observed effects of E2. In this study we show indiscriminate participation of estradiol receptor α (ERα), -β (ERβ) and G- protein coupled estrogen receptor 1 (GPER1) in the mediation of E2 actions in hippocampal synaptosomes of male rats. Synaptic NTPDase1-3 activities are modulated only through activation of ERβ, while activation of ERα, -β and/or non-classical GPER1 decreases synaptic eN activity. Since both ATP and adenosine function as neuromodulators in the hippocampal networks, influencing its function, profound knowledge of mechanisms by which ectonucleotidases are regulated/modulated is of great importance. © 2019 Elsevier B.V.",
journal = "Neuroscience Letters",
title = "Estrogen receptors modulate ectonucleotidases activity in hippocampal synaptosomes of male rats",
volume = "712",
pages = "134474",
doi = "10.1016/j.neulet.2019.134474"
}

Mitrović, N. Lj., Dragić, M., Zarić, M., Drakulić, D. R., Nedeljković, N.,& Grković, I.. (2019). Estrogen receptors modulate ectonucleotidases activity in hippocampal synaptosomes of male rats. in Neuroscience Letters, 712, 134474.
https://doi.org/10.1016/j.neulet.2019.134474

Mitrović NL, Dragić M, Zarić M, Drakulić DR, Nedeljković N, Grković I. Estrogen receptors modulate ectonucleotidases activity in hippocampal synaptosomes of male rats. in Neuroscience Letters. 2019;712:134474.
doi:10.1016/j.neulet.2019.134474 .

Mitrović, Nataša Lj., Dragić, Milorad, Zarić, Marina, Drakulić, Dunja R., Nedeljković, Nadežda, Grković, Ivana, "Estrogen receptors modulate ectonucleotidases activity in hippocampal synaptosomes of male rats" in Neuroscience Letters, 712 (2019):134474,
https://doi.org/10.1016/j.neulet.2019.134474 . .

TY  - JOUR
AU  - Dragić, Milorad
AU  - Zarić, Marina
AU  - Mitrović, Nataša Lj.
AU  - Nedeljković, Nadežda
AU  - Grković, Ivana
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8647
AB  - Astrocytes comprise a heterogenic group of glial cells, which perform homeostatic functions in the central nervous system. These cells react to all kind of insults by changing the morphology and function that result in a transition from the quiescent to a reactive phenotype. Trimethyltin (TMT) intoxication, which reproduces pathological events in the hippocampus similar to those associated with seizures and cognitive decline, has been proven as a useful model for studying responses of the glial cells to neurodegeneration. In the present study, we have explored morphological varieties of astrocytes in the hippocampal subregions of ovariectomized female rats exposed to TMT. We have demonstrated an early loss of neurons in CA1 and DG subfields. Distinct morphotypes of protoplasmic astrocytes observed in CA1/CA3 and the hilus of control animals developed different responses to TMT intoxication, as assessed by GFAP-immunohistochemistry. In CA1 subregion, GFAP+ astrocytes preserved their domain organization and responded with typical hypertrophy, while the hilar GFAP+ astrocytes developed atrophy-like phenotype and increased expression of vimentin and nestin 7 days after the exposure. Both reactive and atrophied-like astrocytes expressed Kir4.1 in CA1/CA3 and the hilus of DG, respectively, indicating that these cells did not change their potential for normal activity at this time point of pathology. Together, the results demonstrate the persistence of two protoplasmic morphotypes of astrocytes, with distinct appearance, function, and fate after TMT-induced neurodegeneration, suggesting their pleiotropic roles in the hippocampal response to neurodegeneration. © 2019 IBRO
T2  - Neuroscience
T1  - Two Distinct Hippocampal Astrocyte Morphotypes Reveal Subfield-Different Fate during Neurodegeneration Induced by Trimethyltin Intoxication
VL  - 423
SP  - 38
EP  - 54
DO  - 10.1016/j.neuroscience.2019.10.022
ER  - 

@article{
author = "Dragić, Milorad and Zarić, Marina and Mitrović, Nataša Lj. and Nedeljković, Nadežda and Grković, Ivana",
year = "2019",
abstract = "Astrocytes comprise a heterogenic group of glial cells, which perform homeostatic functions in the central nervous system. These cells react to all kind of insults by changing the morphology and function that result in a transition from the quiescent to a reactive phenotype. Trimethyltin (TMT) intoxication, which reproduces pathological events in the hippocampus similar to those associated with seizures and cognitive decline, has been proven as a useful model for studying responses of the glial cells to neurodegeneration. In the present study, we have explored morphological varieties of astrocytes in the hippocampal subregions of ovariectomized female rats exposed to TMT. We have demonstrated an early loss of neurons in CA1 and DG subfields. Distinct morphotypes of protoplasmic astrocytes observed in CA1/CA3 and the hilus of control animals developed different responses to TMT intoxication, as assessed by GFAP-immunohistochemistry. In CA1 subregion, GFAP+ astrocytes preserved their domain organization and responded with typical hypertrophy, while the hilar GFAP+ astrocytes developed atrophy-like phenotype and increased expression of vimentin and nestin 7 days after the exposure. Both reactive and atrophied-like astrocytes expressed Kir4.1 in CA1/CA3 and the hilus of DG, respectively, indicating that these cells did not change their potential for normal activity at this time point of pathology. Together, the results demonstrate the persistence of two protoplasmic morphotypes of astrocytes, with distinct appearance, function, and fate after TMT-induced neurodegeneration, suggesting their pleiotropic roles in the hippocampal response to neurodegeneration. © 2019 IBRO",
journal = "Neuroscience",
title = "Two Distinct Hippocampal Astrocyte Morphotypes Reveal Subfield-Different Fate during Neurodegeneration Induced by Trimethyltin Intoxication",
volume = "423",
pages = "38-54",
doi = "10.1016/j.neuroscience.2019.10.022"
}

Dragić, M., Zarić, M., Mitrović, N. Lj., Nedeljković, N.,& Grković, I.. (2019). Two Distinct Hippocampal Astrocyte Morphotypes Reveal Subfield-Different Fate during Neurodegeneration Induced by Trimethyltin Intoxication. in Neuroscience, 423, 38-54.
https://doi.org/10.1016/j.neuroscience.2019.10.022

Dragić M, Zarić M, Mitrović NL, Nedeljković N, Grković I. Two Distinct Hippocampal Astrocyte Morphotypes Reveal Subfield-Different Fate during Neurodegeneration Induced by Trimethyltin Intoxication. in Neuroscience. 2019;423:38-54.
doi:10.1016/j.neuroscience.2019.10.022 .

Dragić, Milorad, Zarić, Marina, Mitrović, Nataša Lj., Nedeljković, Nadežda, Grković, Ivana, "Two Distinct Hippocampal Astrocyte Morphotypes Reveal Subfield-Different Fate during Neurodegeneration Induced by Trimethyltin Intoxication" in Neuroscience, 423 (2019):38-54,
https://doi.org/10.1016/j.neuroscience.2019.10.022 . .

TY  - JOUR
AU  - Zarić, Marina
AU  - Drakulić, Dunja R.
AU  - Guševac Stojanović, Ivana
AU  - Mitrović, Nataša Lj.
AU  - Grković, Ivana
AU  - Martinović, Jelena
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/7626
AB  - Excessive glutamate efflux and N-methyl-D-aspartate receptor (NMDAR) over -activation represent wellknown hallmarks of cerebral ischemia/reperfusion (I/R) injury, still, expression of proteins involved in this aspect of I/R pathophysiology show inconsistent data. Neurosteroid dehydroepiandrosterone (DHEA) has been proposed as potent NMDAR modulator, but its influence on I/R-induced changes up to date remains questionable. Therefore, I/R-governed alteration of vesicular glutamate transporter 1 (vGluT1), synaptic NMDAR subunit composition, postsynaptic density protein 95 (PSD-95) and neuronal morphology alone or following DHEA treatment were examined. For that purpose, adult male Wistar rats were treated with a single dose of vehicle or DHEA (20 mg/kg i.p.) 4 h following sham operation or 15 min bilateral common carotid artery occlusion. Western blot was used for analyses of synaptic protein expressions in hippocampus and prefrontal cortex, while neuronal morphology was assessed using Nissl staining. Regional -specific postischemic changes were detected on protein level i.e. signs of neuronal damage in CA1 area was accompanied with hippocampal vGluT1, NR1, NR2B enhancement and PSD-95 decrement, while histological changes observed in layer III were associated with decreased NR1 subunit in prefrontal cortex. Under physiological conditions DHEA had no effect on protein and histological appearance, while in ischemic milieu it restored hippocampal PSD-95 and NR1 in prefrontal cortex to the control level. Along with intact neurons, ones characterized by morphology observed in I/R group were also present. Future studies involving NMDAR-related intracellular signaling and immunohistochemical analysis will reveal precise effects of I/R and DHEA treatment in selected brain regions. (C) 2018 Elsevier B.V. All rights reserved.
T2  - Brain Research
T1  - Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats
VL  - 1688
SP  - 73
EP  - 80
DO  - 10.1016/j.brainres.2018.03.023
ER  - 

@article{
author = "Zarić, Marina and Drakulić, Dunja R. and Guševac Stojanović, Ivana and Mitrović, Nataša Lj. and Grković, Ivana and Martinović, Jelena",
year = "2018",
abstract = "Excessive glutamate efflux and N-methyl-D-aspartate receptor (NMDAR) over -activation represent wellknown hallmarks of cerebral ischemia/reperfusion (I/R) injury, still, expression of proteins involved in this aspect of I/R pathophysiology show inconsistent data. Neurosteroid dehydroepiandrosterone (DHEA) has been proposed as potent NMDAR modulator, but its influence on I/R-induced changes up to date remains questionable. Therefore, I/R-governed alteration of vesicular glutamate transporter 1 (vGluT1), synaptic NMDAR subunit composition, postsynaptic density protein 95 (PSD-95) and neuronal morphology alone or following DHEA treatment were examined. For that purpose, adult male Wistar rats were treated with a single dose of vehicle or DHEA (20 mg/kg i.p.) 4 h following sham operation or 15 min bilateral common carotid artery occlusion. Western blot was used for analyses of synaptic protein expressions in hippocampus and prefrontal cortex, while neuronal morphology was assessed using Nissl staining. Regional -specific postischemic changes were detected on protein level i.e. signs of neuronal damage in CA1 area was accompanied with hippocampal vGluT1, NR1, NR2B enhancement and PSD-95 decrement, while histological changes observed in layer III were associated with decreased NR1 subunit in prefrontal cortex. Under physiological conditions DHEA had no effect on protein and histological appearance, while in ischemic milieu it restored hippocampal PSD-95 and NR1 in prefrontal cortex to the control level. Along with intact neurons, ones characterized by morphology observed in I/R group were also present. Future studies involving NMDAR-related intracellular signaling and immunohistochemical analysis will reveal precise effects of I/R and DHEA treatment in selected brain regions. (C) 2018 Elsevier B.V. All rights reserved.",
journal = "Brain Research",
title = "Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats",
volume = "1688",
pages = "73-80",
doi = "10.1016/j.brainres.2018.03.023"
}

Zarić, M., Drakulić, D. R., Guševac Stojanović, I., Mitrović, N. Lj., Grković, I.,& Martinović, J.. (2018). Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats. in Brain Research, 1688, 73-80.
https://doi.org/10.1016/j.brainres.2018.03.023

Zarić M, Drakulić DR, Guševac Stojanović I, Mitrović NL, Grković I, Martinović J. Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats. in Brain Research. 2018;1688:73-80.
doi:10.1016/j.brainres.2018.03.023 .

Zarić, Marina, Drakulić, Dunja R., Guševac Stojanović, Ivana, Mitrović, Nataša Lj., Grković, Ivana, Martinović, Jelena, "Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats" in Brain Research, 1688 (2018):73-80,
https://doi.org/10.1016/j.brainres.2018.03.023 . .

TY  - JOUR
AU  - Mitrović, Nataša Lj.
AU  - Zarić, Marina
AU  - Drakulić, Dunja R.
AU  - Martinović, Jelena
AU  - Sevigny, Jean
AU  - Stanojlović, Miloš R.
AU  - Nedeljković, Nadežda
AU  - Grković, Ivana
PY  - 2017
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1459
AB  - 17 beta-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.
T2  - Journal of Molecular Neuroscience
T1  - 17 beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes
VL  - 61
IS  - 3
SP  - 412
EP  - 422
DO  - 10.1007/s12031-016-0877-6
ER  - 

@article{
author = "Mitrović, Nataša Lj. and Zarić, Marina and Drakulić, Dunja R. and Martinović, Jelena and Sevigny, Jean and Stanojlović, Miloš R. and Nedeljković, Nadežda and Grković, Ivana",
year = "2017",
abstract = "17 beta-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.",
journal = "Journal of Molecular Neuroscience",
title = "17 beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes",
volume = "61",
number = "3",
pages = "412-422",
doi = "10.1007/s12031-016-0877-6"
}

Mitrović, N. Lj., Zarić, M., Drakulić, D. R., Martinović, J., Sevigny, J., Stanojlović, M. R., Nedeljković, N.,& Grković, I.. (2017). 17 beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes. in Journal of Molecular Neuroscience, 61(3), 412-422.
https://doi.org/10.1007/s12031-016-0877-6

Mitrović NL, Zarić M, Drakulić DR, Martinović J, Sevigny J, Stanojlović MR, Nedeljković N, Grković I. 17 beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes. in Journal of Molecular Neuroscience. 2017;61(3):412-422.
doi:10.1007/s12031-016-0877-6 .

Mitrović, Nataša Lj., Zarić, Marina, Drakulić, Dunja R., Martinović, Jelena, Sevigny, Jean, Stanojlović, Miloš R., Nedeljković, Nadežda, Grković, Ivana, "17 beta-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes" in Journal of Molecular Neuroscience, 61, no. 3 (2017):412-422,
https://doi.org/10.1007/s12031-016-0877-6 . .