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  - 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  - Francija, Ester
AU  - Lukić, Iva
AU  - Petrović, Zorica
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10580
AB  - Inflammation plays a key role in the pathogenesis of the major depressive disorder. Namely, neuroinflammation can induce the production of neuroactive metabolites that interfere with N-methyl-D-aspartate receptors (NMDAR)-mediated glutamatergic neurotransmission and contribute to depressive-like behaviour. On the other hand, mammalian target of rapamycin (mTOR) activity with synaptogenic effects is the main mediator of antidepressant effects of several potent NMDAR antagonists. In this study, we investigated the specific role of GluN2A subunits of NMDAR on the activity of mTOR signaling and behaviour in lipopolysaccharide (LPS)-induces model of depression. The results showed that mice lacking GluN2A subunit did not display depressive-like behavior after the immune challenge, opposite to LPS-treated wild-type mice. Specifically, in GluN2A knockout mice, we estimated the activity of the mTOR pathway in the hippocampus and prefrontal cortex (PFC) by measuring synaptic levels of upstream regulators (p-Akt, p-ERK, and p-GSK3β) and downstream effectors (p-mTOR, and p-p70S6K) of mTOR activity. In addition, we assessed the changes in the levels of two important synaptic markers, GluA1 and PSD-95. Contrary to downregulated mTOR signaling and decreased synaptic markers in LPS-treated wild-type animals, the resilience of GluN2A KO mice to depressive-like behaviour was paralleled with sustained mTOR signaling activity synaptic stability in hippocampus and PFC. Finally, we disclosed that resistance of GluN2A knockouts to LPS-induced depressive-like behavior was ERK-dependent. These findings demonstrate that GluN2A-ERK-mTOR signaling is a vulnerability factor of inflammation-related depressive behaviour, making this signaling pathway the promising target for developing novel antidepressants.
T2  - Behavioural Brain Research
T1  - GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour
VL  - 417
SP  - 113625
DO  - 10.1016/j.bbr.2021.113625
ER  - 

@article{
author = "Francija, Ester and Lukić, Iva and Petrović, Zorica and Brkić, Željka and Mitić, Miloš and Radulović, Jelena and Adžić, Miroslav",
year = "2022",
abstract = "Inflammation plays a key role in the pathogenesis of the major depressive disorder. Namely, neuroinflammation can induce the production of neuroactive metabolites that interfere with N-methyl-D-aspartate receptors (NMDAR)-mediated glutamatergic neurotransmission and contribute to depressive-like behaviour. On the other hand, mammalian target of rapamycin (mTOR) activity with synaptogenic effects is the main mediator of antidepressant effects of several potent NMDAR antagonists. In this study, we investigated the specific role of GluN2A subunits of NMDAR on the activity of mTOR signaling and behaviour in lipopolysaccharide (LPS)-induces model of depression. The results showed that mice lacking GluN2A subunit did not display depressive-like behavior after the immune challenge, opposite to LPS-treated wild-type mice. Specifically, in GluN2A knockout mice, we estimated the activity of the mTOR pathway in the hippocampus and prefrontal cortex (PFC) by measuring synaptic levels of upstream regulators (p-Akt, p-ERK, and p-GSK3β) and downstream effectors (p-mTOR, and p-p70S6K) of mTOR activity. In addition, we assessed the changes in the levels of two important synaptic markers, GluA1 and PSD-95. Contrary to downregulated mTOR signaling and decreased synaptic markers in LPS-treated wild-type animals, the resilience of GluN2A KO mice to depressive-like behaviour was paralleled with sustained mTOR signaling activity synaptic stability in hippocampus and PFC. Finally, we disclosed that resistance of GluN2A knockouts to LPS-induced depressive-like behavior was ERK-dependent. These findings demonstrate that GluN2A-ERK-mTOR signaling is a vulnerability factor of inflammation-related depressive behaviour, making this signaling pathway the promising target for developing novel antidepressants.",
journal = "Behavioural Brain Research",
title = "GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour",
volume = "417",
pages = "113625",
doi = "10.1016/j.bbr.2021.113625"
}

Francija, E., Lukić, I., Petrović, Z., Brkić, Ž., Mitić, M., Radulović, J.,& Adžić, M.. (2022). GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour. in Behavioural Brain Research, 417, 113625.
https://doi.org/10.1016/j.bbr.2021.113625

Francija E, Lukić I, Petrović Z, Brkić Ž, Mitić M, Radulović J, Adžić M. GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour. in Behavioural Brain Research. 2022;417:113625.
doi:10.1016/j.bbr.2021.113625 .

Francija, Ester, Lukić, Iva, Petrović, Zorica, Brkić, Željka, Mitić, Miloš, Radulović, Jelena, Adžić, Miroslav, "GluN2A-ERK-mTOR pathway confers a vulnerability to LPS-induced depressive-like behaviour" in Behavioural Brain Research, 417 (2022):113625,
https://doi.org/10.1016/j.bbr.2021.113625 . .

TY  - JOUR
AU  - Aleksić, Minja
AU  - Brkić, Željka
AU  - Petrović, Zorica
AU  - Francija, Ester
AU  - Lukić, Iva
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10579
AB  - Adolescent stress predisposes individuals to increased risk for anxiety and depression in adulthood. The stress response is mediated by the glucocorticoid receptor (GR) via regulation of GR-responsive genes involved in brain reaction to stress. Although dysregulation of GR in depression is well documented, this is the first study investigating the role of GRα isoforms in pathogenesis of depression. We exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). Tests evaluating anxiety and depressive-like behaviors were performed at PND70. We analyzed corticosterone concentrations in serum, levels of GRα isoforms (95, 67, 50, 40, and 25 kDa), and mRNA levels of GR-responsive genes (GR, FKBP5, BDNF, and IL-1β) in the hippocampus and the prefrontal cortex (PFC). CUS increased anxiety and depressive-like behavior in adult animals of both sexes, but did not affect corticosterone serum levels, 95 and 67 kDa GR isoforms. However, the levels of shorter GRα isoforms (50, 40, and 25 kDa) were altered in adult mice underwent CUS, in sex- and brain structure–specific way. Changes in gene expression revealed that female depressive-like behavior could be related to increased levels of IL-1β in hippocampus and reduced BDNF levels in both hippocampus and PFC. However, in males, adolescent CUS increased expression of GR in adult hippocampus and BDNF in PFC. These findings suggest that adolescent stress altered levels of GRα isoforms, especially those with lower molecular weight, in sex- and tissue-specific ways, contributing to anxiety and depression in adult mice.
T2  - Journal of Neuroscience Research
T1  - Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice
VL  - 100
IS  - 5
SP  - 1239
EP  - 1253
DO  - 10.1002/jnr.25032
ER  - 

@article{
author = "Aleksić, Minja and Brkić, Željka and Petrović, Zorica and Francija, Ester and Lukić, Iva and Adžić, Miroslav",
year = "2022",
abstract = "Adolescent stress predisposes individuals to increased risk for anxiety and depression in adulthood. The stress response is mediated by the glucocorticoid receptor (GR) via regulation of GR-responsive genes involved in brain reaction to stress. Although dysregulation of GR in depression is well documented, this is the first study investigating the role of GRα isoforms in pathogenesis of depression. We exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). Tests evaluating anxiety and depressive-like behaviors were performed at PND70. We analyzed corticosterone concentrations in serum, levels of GRα isoforms (95, 67, 50, 40, and 25 kDa), and mRNA levels of GR-responsive genes (GR, FKBP5, BDNF, and IL-1β) in the hippocampus and the prefrontal cortex (PFC). CUS increased anxiety and depressive-like behavior in adult animals of both sexes, but did not affect corticosterone serum levels, 95 and 67 kDa GR isoforms. However, the levels of shorter GRα isoforms (50, 40, and 25 kDa) were altered in adult mice underwent CUS, in sex- and brain structure–specific way. Changes in gene expression revealed that female depressive-like behavior could be related to increased levels of IL-1β in hippocampus and reduced BDNF levels in both hippocampus and PFC. However, in males, adolescent CUS increased expression of GR in adult hippocampus and BDNF in PFC. These findings suggest that adolescent stress altered levels of GRα isoforms, especially those with lower molecular weight, in sex- and tissue-specific ways, contributing to anxiety and depression in adult mice.",
journal = "Journal of Neuroscience Research",
title = "Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice",
volume = "100",
number = "5",
pages = "1239-1253",
doi = "10.1002/jnr.25032"
}

Aleksić, M., Brkić, Ž., Petrović, Z., Francija, E., Lukić, I.,& Adžić, M.. (2022). Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice. in Journal of Neuroscience Research, 100(5), 1239-1253.
https://doi.org/10.1002/jnr.25032

Aleksić M, Brkić Ž, Petrović Z, Francija E, Lukić I, Adžić M. Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice. in Journal of Neuroscience Research. 2022;100(5):1239-1253.
doi:10.1002/jnr.25032 .

Aleksić, Minja, Brkić, Željka, Petrović, Zorica, Francija, Ester, Lukić, Iva, Adžić, Miroslav, "Sex-specific contribution of glucocorticoid receptor alpha isoforms to anxiety and depressive-like behavior in mice" in Journal of Neuroscience Research, 100, no. 5 (2022):1239-1253,
https://doi.org/10.1002/jnr.25032 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Živanović, Ana
AU  - Adžić, Miroslav
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9739
AB  - Mitochondria play a significant role in pathogenesis of clinical depression and their function can be impaired by inflammation and alterations in hypothalamic–pituitary–adrenal axis. Sexual context is also a relevant factor in the incidence of mood disorders, and could have a strong influence during an immune challenge. Therefore, in this study we investigated whether the effects of seven-day lipopolysaccharide (LPS) treatment on glucocorticoid receptor (GR) could be associated with apoptosis and alterations in energy metabolism in hippocampus of female and male Wistar rats with depressive-like behavior. To that end, we measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246 in hippocampus of female and male rats, as well as the mRNA levels of two GR-regulated mitochondrial genes, cyclooxygenase -1 and -3 (COX-1 and -3). We also measured alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of hippocampus of these animals, and the levels of cleaved cytosolic poly [ADP-ribose] polymerase-1 (PARP-1) protein. We discovered that even though LPS treatment induced behavioral alterations and affected corticosterone levels and apoptosis in a similar manner in both sexes, it affected mitochondrial GR differently in males and females. Namely, the treatment decreased levels of mitochondrial GR and pGR232/pGR246 ratio only in females, and these alterations were followed by decreased mRNA levels of COX-1 and COX-3 only in this sex. The alterations in COX-1 and COX-3 mRNA levels could indicate impaired oxidative metabolism and diminished mitochondrial function in hippocampus of this sex. © 2020 IBRO
T2  - Neuroscience
T1  - Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression
VL  - 451
SP  - 174
EP  - 183
DO  - 10.1016/j.neuroscience.2020.09.059
ER  - 

@article{
author = "Brkić, Željka and Živanović, Ana and Adžić, Miroslav",
year = "2020",
abstract = "Mitochondria play a significant role in pathogenesis of clinical depression and their function can be impaired by inflammation and alterations in hypothalamic–pituitary–adrenal axis. Sexual context is also a relevant factor in the incidence of mood disorders, and could have a strong influence during an immune challenge. Therefore, in this study we investigated whether the effects of seven-day lipopolysaccharide (LPS) treatment on glucocorticoid receptor (GR) could be associated with apoptosis and alterations in energy metabolism in hippocampus of female and male Wistar rats with depressive-like behavior. To that end, we measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246 in hippocampus of female and male rats, as well as the mRNA levels of two GR-regulated mitochondrial genes, cyclooxygenase -1 and -3 (COX-1 and -3). We also measured alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of hippocampus of these animals, and the levels of cleaved cytosolic poly [ADP-ribose] polymerase-1 (PARP-1) protein. We discovered that even though LPS treatment induced behavioral alterations and affected corticosterone levels and apoptosis in a similar manner in both sexes, it affected mitochondrial GR differently in males and females. Namely, the treatment decreased levels of mitochondrial GR and pGR232/pGR246 ratio only in females, and these alterations were followed by decreased mRNA levels of COX-1 and COX-3 only in this sex. The alterations in COX-1 and COX-3 mRNA levels could indicate impaired oxidative metabolism and diminished mitochondrial function in hippocampus of this sex. © 2020 IBRO",
journal = "Neuroscience",
title = "Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression",
volume = "451",
pages = "174-183",
doi = "10.1016/j.neuroscience.2020.09.059"
}

Brkić, Ž., Živanović, A.,& Adžić, M.. (2020). Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression. in Neuroscience, 451, 174-183.
https://doi.org/10.1016/j.neuroscience.2020.09.059

Brkić Ž, Živanović A, Adžić M. Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression. in Neuroscience. 2020;451:174-183.
doi:10.1016/j.neuroscience.2020.09.059 .

Brkić, Željka, Živanović, Ana, Adžić, Miroslav, "Sex-specific Effects of Lipopolysaccharide on Hippocampal Mitochondrial Processes in Neuroinflammatory Model of Depression" in Neuroscience, 451 (2020):174-183,
https://doi.org/10.1016/j.neuroscience.2020.09.059 . .

TY  - THES
AU  - Brkić, Željka
PY  - 2019
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=7351
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:21603/bdef:Content/download
UR  - https://plus.sr.cobiss.net/opac7/bib/51943439
UR  - http://nardus.mpn.gov.rs/123456789/12180
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8509
AB  - Medijatori inflamacije imaju značajnu ulogu u patogenezi depresije. Jedan od načina na koje inflamacija utiče na nastanak ovog oboljenja jeste putem uticaja na hipotalamo-hipofizno-nadbubrežnu (HPA) osu i krajnje produkate aktivnosti ove ose, glukokortikoide. Glukokortikoidi se u ćelijama vezuju za glukokortikoidni receptor (GR), ligand-zavisan transkripcioni faktor, koji nakon vezivanja glukokortikoida prelazi iz citoplazme u jedro i mitohondrije, gde reguliše ekspresiju velikog broja gena. Aktivnost GR-a je regulisana i kompleksnim obrascem fosforilacija koje mogu da utiču na transkripcionu aktivnost ovog receptora. Pored toga što modulišu ekspresiju jedarnih gena, GR i njegove fosfoforme utiču i na mitohondrijske procese, i na taj način mogu da budu uključeni u proces apoptoze. Značajnu ulogu u nastanku ovog oboljenja ima i pol – kod žena se depresija javlja duplo češće nego kod muškaraca.Uzimajući u obzir navedene podatke, u ovoj tezi je ispitan uticaj sedmodnevnog tretmana inflamatornim agensom, lipopolisaharidom (LPS), na nivoe i fosforilacioni status GR-a u citosolu, jedru i mitohondrijama prefrontalnog korteksa (PFC) i hipokampusa mužjaka i ženki pacova Wistar soja koji pokazuju depresivno ponašanje. Takođe, u citosolu i jedru su praćeni i nivoi košaperona GR-a i kinaza uključenih u njegovu forforilaciju, dok su u citosolu i mitohondrijama praćeni nivoi nekoliko kaspaza i članova BCL-2 proteinske porodice uključenih u regulaciju apoptoze. Dalje, kako bi se utvrdili efekti promena u fosforilaciji na gensku ekspresiju, praćeni su i nivoi iRNK nekoliko jedarnih i mitohondrijskih gena koji su regulisani ovim receptorom i koji su uključeni u parofiziologiju depresije.Rezultati ove studije su pokazali da promene uočene u glukokortikoidnoj signalizaciji izazvane LPS-om utiču na procese uključene u nastanak depresije na tkivno- i polno- specifičan način. Kod mužjaka, poremećaji u glukokortikoidnoj signalizaciji su bili praćeni promenama koje ukazuju na smanjenu neuroplastičnost i neuroinflamaciju i povišenu oksidativnu fosforilaciju u PFC-u. Sa druge strane, promene u glukokortikoidnoj signalizaciji u hipokampusu su bile praćene promenama koje ukazuju na poremećenu serotoninsku neurotransmisiju i narušene neuroendokrine7precese...
AB  - of the ways in which inflammation can influence the onset of this disease is by affecting the activity od hypothalamic-pituitary-adrenal (HPA) axis, and the levels of glucocorticoids, the end-products of the activity of this axis. Glucocorticoids bind to the glucocorticoid receptor (GR), a ligand-dependent transcription factor that, upon glucocorticoid binding, translocates from the cytoplasm to the nucleus, where it regulates the expression of a large number of genes. GR activity is also regulated by a complex pattern of phosphorylations that affect the transcriptional activity of the receptor. In addition to modulating the expression of nuclear genes, GR and its phosphoforms also affect mitochondrial processes, and may be involved in the process of apoptosis. Sex also plays a significant role in the onset of the disease - in women, depression occurs twice as often as in men.Considering these data, in this study we investigated the effect of the seven-day treatment with an inflammatory agent, lipopolysaccharide (LPS), on the levels and phosphorylation status of GR in the cytosol, nucleus and mitochondria of the prefrontal cortex (PFC) and hippocampus of male and female Wistar rats with depressive-like behavior. We also measured the levels of GR co-chaperones and kinases involved in its phosphorylation in cytosol and nucleus, together with the levels of several caspases and members of the BCL-2 protein family involved in the regulation of apoptosis in the cytosol and mitochondria. In order to determine the effects of changes in phosphorylation on gene expression, the mRNA levels of several nuclear and mitochondrial genes regulated by this receptor and involved in the patophysiology of depression were also measured.The results of this study showed that changes observed in glucocorticoid signaling induced by LPS were associated with processes involved in the onset of depression in a tissue- and sex-specific manner. In males, alterations in glucocorticoid signaling were followed by alterations that suggest decreased neuroplasticity and9neuroinflammation, increased oxidative phosphorylation in PFC...
PB  - Универзитет у Београду, Биолошки факултет
T2  - Универзитет у Београду
T1  - Povezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresije
UR  - https://hdl.handle.net/21.15107/rcub_nardus_12180
ER  - 

@phdthesis{
author = "Brkić, Željka",
year = "2019",
abstract = "Medijatori inflamacije imaju značajnu ulogu u patogenezi depresije. Jedan od načina na koje inflamacija utiče na nastanak ovog oboljenja jeste putem uticaja na hipotalamo-hipofizno-nadbubrežnu (HPA) osu i krajnje produkate aktivnosti ove ose, glukokortikoide. Glukokortikoidi se u ćelijama vezuju za glukokortikoidni receptor (GR), ligand-zavisan transkripcioni faktor, koji nakon vezivanja glukokortikoida prelazi iz citoplazme u jedro i mitohondrije, gde reguliše ekspresiju velikog broja gena. Aktivnost GR-a je regulisana i kompleksnim obrascem fosforilacija koje mogu da utiču na transkripcionu aktivnost ovog receptora. Pored toga što modulišu ekspresiju jedarnih gena, GR i njegove fosfoforme utiču i na mitohondrijske procese, i na taj način mogu da budu uključeni u proces apoptoze. Značajnu ulogu u nastanku ovog oboljenja ima i pol – kod žena se depresija javlja duplo češće nego kod muškaraca.Uzimajući u obzir navedene podatke, u ovoj tezi je ispitan uticaj sedmodnevnog tretmana inflamatornim agensom, lipopolisaharidom (LPS), na nivoe i fosforilacioni status GR-a u citosolu, jedru i mitohondrijama prefrontalnog korteksa (PFC) i hipokampusa mužjaka i ženki pacova Wistar soja koji pokazuju depresivno ponašanje. Takođe, u citosolu i jedru su praćeni i nivoi košaperona GR-a i kinaza uključenih u njegovu forforilaciju, dok su u citosolu i mitohondrijama praćeni nivoi nekoliko kaspaza i članova BCL-2 proteinske porodice uključenih u regulaciju apoptoze. Dalje, kako bi se utvrdili efekti promena u fosforilaciji na gensku ekspresiju, praćeni su i nivoi iRNK nekoliko jedarnih i mitohondrijskih gena koji su regulisani ovim receptorom i koji su uključeni u parofiziologiju depresije.Rezultati ove studije su pokazali da promene uočene u glukokortikoidnoj signalizaciji izazvane LPS-om utiču na procese uključene u nastanak depresije na tkivno- i polno- specifičan način. Kod mužjaka, poremećaji u glukokortikoidnoj signalizaciji su bili praćeni promenama koje ukazuju na smanjenu neuroplastičnost i neuroinflamaciju i povišenu oksidativnu fosforilaciju u PFC-u. Sa druge strane, promene u glukokortikoidnoj signalizaciji u hipokampusu su bile praćene promenama koje ukazuju na poremećenu serotoninsku neurotransmisiju i narušene neuroendokrine7precese..., of the ways in which inflammation can influence the onset of this disease is by affecting the activity od hypothalamic-pituitary-adrenal (HPA) axis, and the levels of glucocorticoids, the end-products of the activity of this axis. Glucocorticoids bind to the glucocorticoid receptor (GR), a ligand-dependent transcription factor that, upon glucocorticoid binding, translocates from the cytoplasm to the nucleus, where it regulates the expression of a large number of genes. GR activity is also regulated by a complex pattern of phosphorylations that affect the transcriptional activity of the receptor. In addition to modulating the expression of nuclear genes, GR and its phosphoforms also affect mitochondrial processes, and may be involved in the process of apoptosis. Sex also plays a significant role in the onset of the disease - in women, depression occurs twice as often as in men.Considering these data, in this study we investigated the effect of the seven-day treatment with an inflammatory agent, lipopolysaccharide (LPS), on the levels and phosphorylation status of GR in the cytosol, nucleus and mitochondria of the prefrontal cortex (PFC) and hippocampus of male and female Wistar rats with depressive-like behavior. We also measured the levels of GR co-chaperones and kinases involved in its phosphorylation in cytosol and nucleus, together with the levels of several caspases and members of the BCL-2 protein family involved in the regulation of apoptosis in the cytosol and mitochondria. In order to determine the effects of changes in phosphorylation on gene expression, the mRNA levels of several nuclear and mitochondrial genes regulated by this receptor and involved in the patophysiology of depression were also measured.The results of this study showed that changes observed in glucocorticoid signaling induced by LPS were associated with processes involved in the onset of depression in a tissue- and sex-specific manner. In males, alterations in glucocorticoid signaling were followed by alterations that suggest decreased neuroplasticity and9neuroinflammation, increased oxidative phosphorylation in PFC...",
publisher = "Универзитет у Београду, Биолошки факултет",
journal = "Универзитет у Београду",
title = "Povezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresije",
url = "https://hdl.handle.net/21.15107/rcub_nardus_12180"
}

Brkić, Ž.. (2019). Povezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresije. in Универзитет у Београду
Универзитет у Београду, Биолошки факултет..
https://hdl.handle.net/21.15107/rcub_nardus_12180

Brkić Ž. Povezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresije. in Универзитет у Београду. 2019;.
https://hdl.handle.net/21.15107/rcub_nardus_12180 .

Brkić, Željka, "Povezanost fosforilacionog statusa glukokortikoidnog receptora i ponašanja pacova oba pola u neuroinflamatornom modelu depresije" in Универзитет у Београду (2019),
https://hdl.handle.net/21.15107/rcub_nardus_12180 .

TY  - JOUR
AU  - Francija, Ester
AU  - Petrović, Zorica
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Adžić, Miroslav
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8450
AB  - Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice. These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge. © 2018 Elsevier B.V.
T2  - Behavioural Brain Research
T1  - Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression
VL  - 359
SP  - 550
EP  - 559
DO  - 10.1016/j.bbr.2018.10.011
ER  - 

@article{
author = "Francija, Ester and Petrović, Zorica and Brkić, Željka and Mitić, Miloš and Radulović, Jelena and Adžić, Miroslav",
year = "2019",
abstract = "Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice. These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge. © 2018 Elsevier B.V.",
journal = "Behavioural Brain Research",
title = "Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression",
volume = "359",
pages = "550-559",
doi = "10.1016/j.bbr.2018.10.011"
}

Francija, E., Petrović, Z., Brkić, Ž., Mitić, M., Radulović, J.,& Adžić, M.. (2019). Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. in Behavioural Brain Research, 359, 550-559.
https://doi.org/10.1016/j.bbr.2018.10.011

Francija E, Petrović Z, Brkić Ž, Mitić M, Radulović J, Adžić M. Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. in Behavioural Brain Research. 2019;359:550-559.
doi:10.1016/j.bbr.2018.10.011 .

Francija, Ester, Petrović, Zorica, Brkić, Željka, Mitić, Miloš, Radulović, Jelena, Adžić, Miroslav, "Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression" in Behavioural Brain Research, 359 (2019):550-559,
https://doi.org/10.1016/j.bbr.2018.10.011 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Glavonić, Emilija
AU  - Nešić, Milica J.
AU  - Milosavljević, Minja
AU  - Mihaljević, Marina
AU  - Petrović, Zorica D.
AU  - Pavlović, Zorana
AU  - Brkić, Željka
AU  - Francija, Ester
AU  - Soldatović, Ivan A.
AU  - Mitić, Miloš
AU  - Radulović, Jelena
AU  - Marić, Nađa P.
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8010
AB  - Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.
T2  - Progress in Neuro-Psychopharmacology and Biological Psychiatry
T1  - Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states
VL  - 90
SP  - 288
EP  - 299
DO  - 10.1016/j.pnpbp.2018.12.011
ER  - 

@article{
author = "Adžić, Miroslav and Glavonić, Emilija and Nešić, Milica J. and Milosavljević, Minja and Mihaljević, Marina and Petrović, Zorica D. and Pavlović, Zorana and Brkić, Željka and Francija, Ester and Soldatović, Ivan A. and Mitić, Miloš and Radulović, Jelena and Marić, Nađa P.",
year = "2019",
abstract = "Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα their interactions and FKBP5 explained 22%–35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα and emphasized its role in fear extinction and neural plasticity. © 2018 Elsevier Inc.",
journal = "Progress in Neuro-Psychopharmacology and Biological Psychiatry",
title = "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states",
volume = "90",
pages = "288-299",
doi = "10.1016/j.pnpbp.2018.12.011"
}

Adžić, M., Glavonić, E., Nešić, M. J., Milosavljević, M., Mihaljević, M., Petrović, Z. D., Pavlović, Z., Brkić, Ž., Francija, E., Soldatović, I. A., Mitić, M., Radulović, J.,& Marić, N. P.. (2019). Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90, 288-299.
https://doi.org/10.1016/j.pnpbp.2018.12.011

Adžić M, Glavonić E, Nešić MJ, Milosavljević M, Mihaljević M, Petrović ZD, Pavlović Z, Brkić Ž, Francija E, Soldatović IA, Mitić M, Radulović J, Marić NP. Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states. in Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019;90:288-299.
doi:10.1016/j.pnpbp.2018.12.011 .

Adžić, Miroslav, Glavonić, Emilija, Nešić, Milica J., Milosavljević, Minja, Mihaljević, Marina, Petrović, Zorica D., Pavlović, Zorana, Brkić, Željka, Francija, Ester, Soldatović, Ivan A., Mitić, Miloš, Radulović, Jelena, Marić, Nađa P., "Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states" in Progress in Neuro-Psychopharmacology and Biological Psychiatry, 90 (2019):288-299,
https://doi.org/10.1016/j.pnpbp.2018.12.011 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Milosavljević, Minja
AU  - Glavonić, Emilija
AU  - Adžić, Miroslav
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8359
AB  - Mitochondrial dysfunction can result from the interplay between elevated inflammatory markers and alterations in hypothalamic–pituitary–adrenal (HPA) axis, and can contribute to pathogenesis of major depression. Therefore, in this study we investigated whether the effects of lipopolysaccharide (LPS) on glucocorticoid receptor (GR) could be associated with alterations in mitochondrial apoptotic signaling in the prefrontal cortex of male and female Wistar rats with depressive-like behavior. To that end, we measured LPS-induced alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of PFC of female and male rats, as well as the levels of cleaved cytosolic PARP-1. We also measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246, as well as the mRNA levels of two GR-regulated mitochondrial genes, COX-1 and COX-3. We discovered that although seven-day LPS treatment evoked depressive-like behavior and induced apoptosis in the PFC of both sexes, it affected apoptotic cascades in both sexes differently. In females the treatment initiated both intrinsic and extrinsic apoptotic cascade, while in males only intrinsic cascade was engaged. Alterations in intrinsic apoptotic pathway were more associated with GR alterations in males, where LPS treatment decreased levels of mitochondrial GR and increased pGR232/pGR246 ratio. Alterations in mitochondrial GR could be associated with changes in expression of genes involved in oxidative metabolism in the PFC of this sex, and could, in combination with elevated levels of BCL-2 and decreased levels of BAX detected in this cell fraction, mitigate the detrimental effect of LPS on mitochondria in male PFC. © 2019
T2  - Brain Research Bulletin
T1  - Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor
VL  - 150
SP  - 317
EP  - 327
DO  - 10.1016/j.brainresbull.2019.06.016
ER  - 

@article{
author = "Brkić, Željka and Milosavljević, Minja and Glavonić, Emilija and Adžić, Miroslav",
year = "2019",
abstract = "Mitochondrial dysfunction can result from the interplay between elevated inflammatory markers and alterations in hypothalamic–pituitary–adrenal (HPA) axis, and can contribute to pathogenesis of major depression. Therefore, in this study we investigated whether the effects of lipopolysaccharide (LPS) on glucocorticoid receptor (GR) could be associated with alterations in mitochondrial apoptotic signaling in the prefrontal cortex of male and female Wistar rats with depressive-like behavior. To that end, we measured LPS-induced alterations in the extrinsic and intrinsic apoptotic pathways in mitochondria and cytosol of PFC of female and male rats, as well as the levels of cleaved cytosolic PARP-1. We also measured the mitochondrial levels of GR and its phosphoisoforms pGR232 and pGR246, as well as the mRNA levels of two GR-regulated mitochondrial genes, COX-1 and COX-3. We discovered that although seven-day LPS treatment evoked depressive-like behavior and induced apoptosis in the PFC of both sexes, it affected apoptotic cascades in both sexes differently. In females the treatment initiated both intrinsic and extrinsic apoptotic cascade, while in males only intrinsic cascade was engaged. Alterations in intrinsic apoptotic pathway were more associated with GR alterations in males, where LPS treatment decreased levels of mitochondrial GR and increased pGR232/pGR246 ratio. Alterations in mitochondrial GR could be associated with changes in expression of genes involved in oxidative metabolism in the PFC of this sex, and could, in combination with elevated levels of BCL-2 and decreased levels of BAX detected in this cell fraction, mitigate the detrimental effect of LPS on mitochondria in male PFC. © 2019",
journal = "Brain Research Bulletin",
title = "Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor",
volume = "150",
pages = "317-327",
doi = "10.1016/j.brainresbull.2019.06.016"
}

Brkić, Ž., Milosavljević, M., Glavonić, E.,& Adžić, M.. (2019). Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor. in Brain Research Bulletin, 150, 317-327.
https://doi.org/10.1016/j.brainresbull.2019.06.016

Brkić Ž, Milosavljević M, Glavonić E, Adžić M. Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor. in Brain Research Bulletin. 2019;150:317-327.
doi:10.1016/j.brainresbull.2019.06.016 .

Brkić, Željka, Milosavljević, Minja, Glavonić, Emilija, Adžić, Miroslav, "Mitochondrial signaling in inflammation-induced depressive behavior in female and male rats: The role of glucocorticoid receptor" in Brain Research Bulletin, 150 (2019):317-327,
https://doi.org/10.1016/j.brainresbull.2019.06.016 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Brkić, Željka
AU  - Mitić, Miloš
AU  - Francija, Ester
AU  - Jovičić, Milica J.
AU  - Radulović, Jelena
AU  - Marić, Nađa P.
PY  - 2018
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1939
AB  - Background: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. Methods: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. Results: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. Conclusion: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required.
T2  - Current Neuropharmacology
T1  - Therapeutic Strategies for Treatment of Inflammation-related Depression
VL  - 16
IS  - 2
SP  - 176
EP  - 209
DO  - 10.2174/1570159X15666170828163048
ER  - 

@article{
author = "Adžić, Miroslav and Brkić, Željka and Mitić, Miloš and Francija, Ester and Jovičić, Milica J. and Radulović, Jelena and Marić, Nađa P.",
year = "2018",
abstract = "Background: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. Methods: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. Results: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. Conclusion: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required.",
journal = "Current Neuropharmacology",
title = "Therapeutic Strategies for Treatment of Inflammation-related Depression",
volume = "16",
number = "2",
pages = "176-209",
doi = "10.2174/1570159X15666170828163048"
}

Adžić, M., Brkić, Ž., Mitić, M., Francija, E., Jovičić, M. J., Radulović, J.,& Marić, N. P.. (2018). Therapeutic Strategies for Treatment of Inflammation-related Depression. in Current Neuropharmacology, 16(2), 176-209.
https://doi.org/10.2174/1570159X15666170828163048

Adžić M, Brkić Ž, Mitić M, Francija E, Jovičić MJ, Radulović J, Marić NP. Therapeutic Strategies for Treatment of Inflammation-related Depression. in Current Neuropharmacology. 2018;16(2):176-209.
doi:10.2174/1570159X15666170828163048 .

Adžić, Miroslav, Brkić, Željka, Mitić, Miloš, Francija, Ester, Jovičić, Milica J., Radulović, Jelena, Marić, Nađa P., "Therapeutic Strategies for Treatment of Inflammation-related Depression" in Current Neuropharmacology, 16, no. 2 (2018):176-209,
https://doi.org/10.2174/1570159X15666170828163048 . .

TY  - JOUR
AU  - Mitić, Miloš
AU  - Brkić, Željka
AU  - Lukić, Iva
AU  - Adžić, Miroslav
PY  - 2017
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1695
AB  - Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3 beta, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3 beta-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3 beta targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3 beta-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3 beta-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3 beta activity. On the other hand, fluoxetine managed to up regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3 beta pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males.
T2  - Behavioural Brain Research
T1  - Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats
VL  - 333
SP  - 295
EP  - 303
DO  - 10.1016/j.bbr.2017.07.014
ER  - 

@article{
author = "Mitić, Miloš and Brkić, Željka and Lukić, Iva and Adžić, Miroslav",
year = "2017",
abstract = "Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3 beta, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3 beta-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3 beta targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3 beta-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3 beta-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3 beta activity. On the other hand, fluoxetine managed to up regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3 beta pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males.",
journal = "Behavioural Brain Research",
title = "Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats",
volume = "333",
pages = "295-303",
doi = "10.1016/j.bbr.2017.07.014"
}

Mitić, M., Brkić, Ž., Lukić, I.,& Adžić, M.. (2017). Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats. in Behavioural Brain Research, 333, 295-303.
https://doi.org/10.1016/j.bbr.2017.07.014

Mitić M, Brkić Ž, Lukić I, Adžić M. Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats. in Behavioural Brain Research. 2017;333:295-303.
doi:10.1016/j.bbr.2017.07.014 .

Mitić, Miloš, Brkić, Željka, Lukić, Iva, Adžić, Miroslav, "Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats" in Behavioural Brain Research, 333 (2017):295-303,
https://doi.org/10.1016/j.bbr.2017.07.014 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Francija, Ester
AU  - Petrović, Zorica D.
AU  - Franić, Dušanka
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Adžić, Miroslav
PY  - 2017
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1888
AB  - Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently-in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor-associated processes involved in depressive-like behaviour in males and females.
T2  - Journal of Psychopharmacology
T1  - Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats
VL  - 31
IS  - 9
SP  - 1234
EP  - 1249
DO  - 10.1177/0269881117725914
ER  - 

@article{
author = "Brkić, Željka and Francija, Ester and Petrović, Zorica D. and Franić, Dušanka and Lukić, Iva and Mitić, Miloš and Adžić, Miroslav",
year = "2017",
abstract = "Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently-in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor-associated processes involved in depressive-like behaviour in males and females.",
journal = "Journal of Psychopharmacology",
title = "Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats",
volume = "31",
number = "9",
pages = "1234-1249",
doi = "10.1177/0269881117725914"
}

Brkić, Ž., Francija, E., Petrović, Z. D., Franić, D., Lukić, I., Mitić, M.,& Adžić, M.. (2017). Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats. in Journal of Psychopharmacology, 31(9), 1234-1249.
https://doi.org/10.1177/0269881117725914

Brkić Ž, Francija E, Petrović ZD, Franić D, Lukić I, Mitić M, Adžić M. Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats. in Journal of Psychopharmacology. 2017;31(9):1234-1249.
doi:10.1177/0269881117725914 .

Brkić, Željka, Francija, Ester, Petrović, Zorica D., Franić, Dušanka, Lukić, Iva, Mitić, Miloš, Adžić, Miroslav, "Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats" in Journal of Psychopharmacology, 31, no. 9 (2017):1234-1249,
https://doi.org/10.1177/0269881117725914 . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Brkić, Željka
AU  - Bulajić, Sonja
AU  - Mitić, Miloš
AU  - Radojčić, Marija
PY  - 2016
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1304
AB  - Mitochondria are cell organelles crucial to the production of cellular energy. Several lines of evidence have indicated that mitochondrial dysfunction could be related to the pathophysiology of CNS diseases including bipolar disorder, major depressive disorder, and schizophrenia. These changes include impaired energy metabolism in the brain, co-morbidity with mitochondrial diseases, the effects of psychotropics on mitochondrial function, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA polymorphisms. Additionally, psychotropic drug treatments can alter energy metabolism and may affect mitochondrial processes. This review focuses on recent findings regarding the effects of antidepressants on mitochondrial processes in psychiatric disorders. Drug Dev Res 77 : 400-406, 2016. (c) 2016 Wiley Periodicals, Inc.
T2  - Drug Development Research
T1  - Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders
VL  - 77
IS  - 7
SP  - 400
EP  - 406
DO  - 10.1002/ddr.21332
ER  - 

@article{
author = "Adžić, Miroslav and Brkić, Željka and Bulajić, Sonja and Mitić, Miloš and Radojčić, Marija",
year = "2016",
abstract = "Mitochondria are cell organelles crucial to the production of cellular energy. Several lines of evidence have indicated that mitochondrial dysfunction could be related to the pathophysiology of CNS diseases including bipolar disorder, major depressive disorder, and schizophrenia. These changes include impaired energy metabolism in the brain, co-morbidity with mitochondrial diseases, the effects of psychotropics on mitochondrial function, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA polymorphisms. Additionally, psychotropic drug treatments can alter energy metabolism and may affect mitochondrial processes. This review focuses on recent findings regarding the effects of antidepressants on mitochondrial processes in psychiatric disorders. Drug Dev Res 77 : 400-406, 2016. (c) 2016 Wiley Periodicals, Inc.",
journal = "Drug Development Research",
title = "Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders",
volume = "77",
number = "7",
pages = "400-406",
doi = "10.1002/ddr.21332"
}

Adžić, M., Brkić, Ž., Bulajić, S., Mitić, M.,& Radojčić, M.. (2016). Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders. in Drug Development Research, 77(7), 400-406.
https://doi.org/10.1002/ddr.21332

Adžić M, Brkić Ž, Bulajić S, Mitić M, Radojčić M. Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders. in Drug Development Research. 2016;77(7):400-406.
doi:10.1002/ddr.21332 .

Adžić, Miroslav, Brkić, Željka, Bulajić, Sonja, Mitić, Miloš, Radojčić, Marija, "Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders" in Drug Development Research, 77, no. 7 (2016):400-406,
https://doi.org/10.1002/ddr.21332 . .

TY  - JOUR
AU  - Brkić, Željka
AU  - Petrović, Zorica D.
AU  - Franić, Dušanka
AU  - Mitić, Miloš
AU  - Adžić, Miroslav
PY  - 2016
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/1218
AB  - Inflammation plays a key role in the pathogenesis of major depressive disorder (MDD) for a subset of depressed individuals. One of the possible routes by which cytokines can induce depressive symptoms is by promoting the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis via altering glucocorticoid receptor (GR) function. We investigated the mechanisms that finely tune the GR functioning upon lipopolysaccharide (LPS), i.e., subcellular localization of the GR, the levels of its co-chaperones FK506 binding protein 52 (FKBP4) and FK506 binding protein 51 (FKBP5), the receptor phosphorylation status along with its upstream kinases, as well as mRNA levels of GR-regulated genes in the prefrontal cortex (PFC) of male and female Wistar rats. We found that upon LPS treatment, animals of both sexes exhibited depressive-like behavior and elevated serum corticosterone. However, the nuclear translocation of the GR and both FKBPs was found only in males, together with elevated phosphorylation of the GR at serine 232 and 246 and the activation and nuclear translocation of all analyzed kinases. This activation of the GR in males was paralleled with altered expression of GR-related genes, particularly PTGS2 and BDNF. Our data suggest that LPS treatment produced alterations in the mechanisms that control the GR nuclear translocation in the PFC of males, and that these mechanisms may contribute to the sex-specific dysfunction of GR-related neurotrophic and neuroinflammatory processes in inflammation-associated depression.
T2  - Psychopharmacology
T1  - Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats
VL  - 233
IS  - 18
SP  - 3315
EP  - 3330
DO  - 10.1007/s00213-016-4374-y
ER  - 

@article{
author = "Brkić, Željka and Petrović, Zorica D. and Franić, Dušanka and Mitić, Miloš and Adžić, Miroslav",
year = "2016",
abstract = "Inflammation plays a key role in the pathogenesis of major depressive disorder (MDD) for a subset of depressed individuals. One of the possible routes by which cytokines can induce depressive symptoms is by promoting the dysregulation of hypothalamic-pituitary-adrenal (HPA) axis via altering glucocorticoid receptor (GR) function. We investigated the mechanisms that finely tune the GR functioning upon lipopolysaccharide (LPS), i.e., subcellular localization of the GR, the levels of its co-chaperones FK506 binding protein 52 (FKBP4) and FK506 binding protein 51 (FKBP5), the receptor phosphorylation status along with its upstream kinases, as well as mRNA levels of GR-regulated genes in the prefrontal cortex (PFC) of male and female Wistar rats. We found that upon LPS treatment, animals of both sexes exhibited depressive-like behavior and elevated serum corticosterone. However, the nuclear translocation of the GR and both FKBPs was found only in males, together with elevated phosphorylation of the GR at serine 232 and 246 and the activation and nuclear translocation of all analyzed kinases. This activation of the GR in males was paralleled with altered expression of GR-related genes, particularly PTGS2 and BDNF. Our data suggest that LPS treatment produced alterations in the mechanisms that control the GR nuclear translocation in the PFC of males, and that these mechanisms may contribute to the sex-specific dysfunction of GR-related neurotrophic and neuroinflammatory processes in inflammation-associated depression.",
journal = "Psychopharmacology",
title = "Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats",
volume = "233",
number = "18",
pages = "3315-3330",
doi = "10.1007/s00213-016-4374-y"
}

Brkić, Ž., Petrović, Z. D., Franić, D., Mitić, M.,& Adžić, M.. (2016). Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats. in Psychopharmacology, 233(18), 3315-3330.
https://doi.org/10.1007/s00213-016-4374-y

Brkić Ž, Petrović ZD, Franić D, Mitić M, Adžić M. Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats. in Psychopharmacology. 2016;233(18):3315-3330.
doi:10.1007/s00213-016-4374-y .

Brkić, Željka, Petrović, Zorica D., Franić, Dušanka, Mitić, Miloš, Adžić, Miroslav, "Male-specific effects of lipopolysaccharide on glucocorticoid receptor nuclear translocation in the prefrontal cortex of depressive rats" in Psychopharmacology, 233, no. 18 (2016):3315-3330,
https://doi.org/10.1007/s00213-016-4374-y . .

TY  - JOUR
AU  - Adžić, Miroslav
AU  - Đorđević, Jelena D.
AU  - Mitić, Miloš
AU  - Brkić, Željka
AU  - Lukić, Iva
AU  - Radojčić, Marija
PY  - 2015
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/670
AB  - Peripheral inflammation induced by lipopolysaccharide (LPS) causes behavioural changes indicative for depression. The possible mechanisms involve the interference with neuroinflammatory, neuroendocrine, and neurotrophic processes. Apart from heterogeneity in the molecular background, sexual context may be another factor relevant to the manifestation of mood disturbances upon an immune challenge. We investigated sex-dependent effects of a 7-day LPS treatment of adult Wistar rats on depressive-like behaviour and their relation with hypothalamic neuroendocrine factor, corticotrophin-releasing hormone (CRH), proplastic brain-derived neurotropic factor (BDNF), pro-inflammatory cyclooxygenase-2 (COX-2) and nuclear factor kappa beta (NFkB). Also, their regulators, the glucocorticoid receptor (GR) and CCAAT enhancer-binding protein (C/EBP) beta were followed. LPS induced depressive-like behaviour in females was associated with the increased hypothalamic CRH and decreased BDNF, but not with COX-2. These changes were paralleled by an increase in nuclear GR, NFkB and 20 kDa C/EBP beta. LPS also altered behaviour in males and increased CRH expression, but in contrast to females, this was accompanied with the elevated COX-2, accumulation of cytosolic GR and elevated nuclear 38 kDa C/EBP beta and NFkB. In conclusion, depressive-like phenotype induced by LPS in both sexes emerges from similar HPA axis activation and sex-specific alterations of hypothalamic molecular signalling: in males it is related to compromised control of neuroinflamation connected with cytoplasmic GR retention, while in females it is related to diminished proplastic capacity of BDNF. Sex-dependent mechanisms by which inflammation alters hypothalamic processes and cause pathological behaviour in animals, could be operative in the treatment of depression-related brain inflammation. (C) 2015 Elsevier B.V. All rights reserved.
T2  - Behavioural Brain Research
T1  - The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta
VL  - 291
SP  - 130
EP  - 139
DO  - 10.1016/j.bbr.2015.05.029
ER  - 

@article{
author = "Adžić, Miroslav and Đorđević, Jelena D. and Mitić, Miloš and Brkić, Željka and Lukić, Iva and Radojčić, Marija",
year = "2015",
abstract = "Peripheral inflammation induced by lipopolysaccharide (LPS) causes behavioural changes indicative for depression. The possible mechanisms involve the interference with neuroinflammatory, neuroendocrine, and neurotrophic processes. Apart from heterogeneity in the molecular background, sexual context may be another factor relevant to the manifestation of mood disturbances upon an immune challenge. We investigated sex-dependent effects of a 7-day LPS treatment of adult Wistar rats on depressive-like behaviour and their relation with hypothalamic neuroendocrine factor, corticotrophin-releasing hormone (CRH), proplastic brain-derived neurotropic factor (BDNF), pro-inflammatory cyclooxygenase-2 (COX-2) and nuclear factor kappa beta (NFkB). Also, their regulators, the glucocorticoid receptor (GR) and CCAAT enhancer-binding protein (C/EBP) beta were followed. LPS induced depressive-like behaviour in females was associated with the increased hypothalamic CRH and decreased BDNF, but not with COX-2. These changes were paralleled by an increase in nuclear GR, NFkB and 20 kDa C/EBP beta. LPS also altered behaviour in males and increased CRH expression, but in contrast to females, this was accompanied with the elevated COX-2, accumulation of cytosolic GR and elevated nuclear 38 kDa C/EBP beta and NFkB. In conclusion, depressive-like phenotype induced by LPS in both sexes emerges from similar HPA axis activation and sex-specific alterations of hypothalamic molecular signalling: in males it is related to compromised control of neuroinflamation connected with cytoplasmic GR retention, while in females it is related to diminished proplastic capacity of BDNF. Sex-dependent mechanisms by which inflammation alters hypothalamic processes and cause pathological behaviour in animals, could be operative in the treatment of depression-related brain inflammation. (C) 2015 Elsevier B.V. All rights reserved.",
journal = "Behavioural Brain Research",
title = "The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta",
volume = "291",
pages = "130-139",
doi = "10.1016/j.bbr.2015.05.029"
}

Adžić, M., Đorđević, J. D., Mitić, M., Brkić, Ž., Lukić, I.,& Radojčić, M.. (2015). The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta. in Behavioural Brain Research, 291, 130-139.
https://doi.org/10.1016/j.bbr.2015.05.029

Adžić M, Đorđević JD, Mitić M, Brkić Ž, Lukić I, Radojčić M. The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta. in Behavioural Brain Research. 2015;291:130-139.
doi:10.1016/j.bbr.2015.05.029 .

Adžić, Miroslav, Đorđević, Jelena D., Mitić, Miloš, Brkić, Željka, Lukić, Iva, Radojčić, Marija, "The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-beta" in Behavioural Brain Research, 291 (2015):130-139,
https://doi.org/10.1016/j.bbr.2015.05.029 . .

TY  - CONF
AU  - Brkić, Željka
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Božović, N.
AU  - Brašanac, Jelena
AU  - Đorđević, Jelena
AU  - Adžić, Miroslav
PY  - 2014
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9192
AB  - Systemic exposure to inflammatory challenges, such as lipopolysaccharide
(LPS), can induce a central neuroinflammation, which has been associated
with the development of major depressive disorder (MDD). Research data
emphasize not only sex as an important factor in the pathogenesis of MDD
but also point out a disturbance in cyclin-dependent kinase 5 (CDK5)
pathway. Therefore, in this study, we investigated the effects of LPS
treatment on depressive-like behavior as well as on the CDK5 and p35
levels in the cytosol and the nucleus of the prefrontal cortex of Wistar rats.
Our results showed that LPS causes a depressive-like behavior in both
sexes, as well as significant changes in the levels of CDK5 and p35, but
only in the males. Such differences of CDK5 activity could contribute to the
development of depressive-like behavior in males, while in females it seems
that some other mechanisms could be involved in the induction of this
behavior.
PB  - Society of Physical Chemists of Serbia
C3  - Physical chemistry 2014: 12th International Conference on Fundamental and Applied Aspects of Physical Chemistry
T1  - Involvement of prefrontal cortex cdk5 pathway in lps-induced depressive-like behavior in male and female wistar rats
VL  - F-12-P
UR  - https://hdl.handle.net/21.15107/rcub_vinar_9192
ER  - 

@conference{
author = "Brkić, Željka and Lukić, Iva and Mitić, Miloš and Božović, N. and Brašanac, Jelena and Đorđević, Jelena and Adžić, Miroslav",
year = "2014",
abstract = "Systemic exposure to inflammatory challenges, such as lipopolysaccharide
(LPS), can induce a central neuroinflammation, which has been associated
with the development of major depressive disorder (MDD). Research data
emphasize not only sex as an important factor in the pathogenesis of MDD
but also point out a disturbance in cyclin-dependent kinase 5 (CDK5)
pathway. Therefore, in this study, we investigated the effects of LPS
treatment on depressive-like behavior as well as on the CDK5 and p35
levels in the cytosol and the nucleus of the prefrontal cortex of Wistar rats.
Our results showed that LPS causes a depressive-like behavior in both
sexes, as well as significant changes in the levels of CDK5 and p35, but
only in the males. Such differences of CDK5 activity could contribute to the
development of depressive-like behavior in males, while in females it seems
that some other mechanisms could be involved in the induction of this
behavior.",
publisher = "Society of Physical Chemists of Serbia",
journal = "Physical chemistry 2014: 12th International Conference on Fundamental and Applied Aspects of Physical Chemistry",
title = "Involvement of prefrontal cortex cdk5 pathway in lps-induced depressive-like behavior in male and female wistar rats",
volume = "F-12-P",
url = "https://hdl.handle.net/21.15107/rcub_vinar_9192"
}

Brkić, Ž., Lukić, I., Mitić, M., Božović, N., Brašanac, J., Đorđević, J.,& Adžić, M.. (2014). Involvement of prefrontal cortex cdk5 pathway in lps-induced depressive-like behavior in male and female wistar rats. in Physical chemistry 2014: 12th International Conference on Fundamental and Applied Aspects of Physical Chemistry
Society of Physical Chemists of Serbia., F-12-P.
https://hdl.handle.net/21.15107/rcub_vinar_9192

Brkić Ž, Lukić I, Mitić M, Božović N, Brašanac J, Đorđević J, Adžić M. Involvement of prefrontal cortex cdk5 pathway in lps-induced depressive-like behavior in male and female wistar rats. in Physical chemistry 2014: 12th International Conference on Fundamental and Applied Aspects of Physical Chemistry. 2014;F-12-P.
https://hdl.handle.net/21.15107/rcub_vinar_9192 .

Brkić, Željka, Lukić, Iva, Mitić, Miloš, Božović, N., Brašanac, Jelena, Đorđević, Jelena, Adžić, Miroslav, "Involvement of prefrontal cortex cdk5 pathway in lps-induced depressive-like behavior in male and female wistar rats" in Physical chemistry 2014: 12th International Conference on Fundamental and Applied Aspects of Physical Chemistry, F-12-P (2014),
https://hdl.handle.net/21.15107/rcub_vinar_9192 .