TY  - JOUR
AU  - Zeljković Jovanović, Milica
AU  - Stanojević, Jelena
AU  - Stevanović, Ivana
AU  - Stekić, Anđela
AU  - Bolland, Samuel J.
AU  - Jasnić, Nebojša
AU  - Ninković, Milica
AU  - Zarić Kontić, Marina
AU  - Ilić, Tihomir V.
AU  - Rodger, Jennifer
AU  - Nedeljković, Nadežda
AU  - Dragić, Milorad
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11099
AB  - Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits. © 2023 by the authors.
T2  - Cells
T1  - Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease
VL  - 12
IS  - 11
DO  - 10.3390/cells12111525
ER  - 

@article{
author = "Zeljković Jovanović, Milica and Stanojević, Jelena and Stevanović, Ivana and Stekić, Anđela and Bolland, Samuel J. and Jasnić, Nebojša and Ninković, Milica and Zarić Kontić, Marina and Ilić, Tihomir V. and Rodger, Jennifer and Nedeljković, Nadežda and Dragić, Milorad",
year = "2023",
abstract = "Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits. © 2023 by the authors.",
journal = "Cells",
title = "Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease",
volume = "12",
number = "11",
doi = "10.3390/cells12111525"
}

Zeljković Jovanović, M., Stanojević, J., Stevanović, I., Stekić, A., Bolland, S. J., Jasnić, N., Ninković, M., Zarić Kontić, M., Ilić, T. V., Rodger, J., Nedeljković, N.,& Dragić, M.. (2023). Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease. in Cells, 12(11).
https://doi.org/10.3390/cells12111525

Zeljković Jovanović M, Stanojević J, Stevanović I, Stekić A, Bolland SJ, Jasnić N, Ninković M, Zarić Kontić M, Ilić TV, Rodger J, Nedeljković N, Dragić M. Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease. in Cells. 2023;12(11).
doi:10.3390/cells12111525 .

Zeljković Jovanović, Milica, Stanojević, Jelena, Stevanović, Ivana, Stekić, Anđela, Bolland, Samuel J., Jasnić, Nebojša, Ninković, Milica, Zarić Kontić, Marina, Ilić, Tihomir V., Rodger, Jennifer, Nedeljković, Nadežda, Dragić, Milorad, "Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson’s Disease" in Cells, 12, no. 11 (2023),
https://doi.org/10.3390/cells12111525 . .

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  - 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 . .