TY  - JOUR
AU  - Mitić, Miloš
AU  - Lukić, Iva
AU  - Božović, Natalija
AU  - Đorđević, Jelena D.
AU  - Adžić, Miroslav
PY  - 2015
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/861
AB  - Considerable evidence shows an association of depression with the immune system and emphasizes the importance of gender in the etiology of the disease and the response to inflammatory stimuli. We examined the influence of immune-challenged systems on depressive-like behavior in female rats in the context of gonadal hormones. We used a neuroinflammatory model of depression elicited by lipopolysaccharide (LPS) administration on naive and ovariectomized (OVX) female rats, and examined the effects of estradiol (E2) and/or progesterone (P4) replacement therapy on animal behavior, as assessed by the forced swimming test (FST). We found that LPS and OVX increase immobility in the FST, while LPS also decreased body weight in naive female rats. Further, even though P4 application alone showed beneficial effects on the behavioral profile (it reduced immobility and increased climbing), supplementation of both hormones (E2 and P4) together to OVX rats failed to do so. When OVX rats were exposed to LPS-induced immune challenge, neither hormone individually nor their combination had any effect on immobility, however, their joint supplementation increased climbing behavior. In conclusion, our study confirmed that both LPS and OVX induced depressive-like behavior in female rats. Furthermore, our results potentiate P4 supplementation in relieving the depressive-like symptomatology in OVX rats, most likely through fine-tuning of different neurotransmitter systems. In the context of an activated immune system, the application of E2 and/or P4 does not provide any advantageous effects on depressive-like behavior.
T2  - Archives of Biological Sciences
T1  - Effects of Female Gonadal Hormones and Lps on Depressive-Like Behavior in Rats
VL  - 67
IS  - 3
SP  - 1025
EP  - 1032
DO  - 10.2298/ABS150130065M
ER  - 

@article{
author = "Mitić, Miloš and Lukić, Iva and Božović, Natalija and Đorđević, Jelena D. and Adžić, Miroslav",
year = "2015",
abstract = "Considerable evidence shows an association of depression with the immune system and emphasizes the importance of gender in the etiology of the disease and the response to inflammatory stimuli. We examined the influence of immune-challenged systems on depressive-like behavior in female rats in the context of gonadal hormones. We used a neuroinflammatory model of depression elicited by lipopolysaccharide (LPS) administration on naive and ovariectomized (OVX) female rats, and examined the effects of estradiol (E2) and/or progesterone (P4) replacement therapy on animal behavior, as assessed by the forced swimming test (FST). We found that LPS and OVX increase immobility in the FST, while LPS also decreased body weight in naive female rats. Further, even though P4 application alone showed beneficial effects on the behavioral profile (it reduced immobility and increased climbing), supplementation of both hormones (E2 and P4) together to OVX rats failed to do so. When OVX rats were exposed to LPS-induced immune challenge, neither hormone individually nor their combination had any effect on immobility, however, their joint supplementation increased climbing behavior. In conclusion, our study confirmed that both LPS and OVX induced depressive-like behavior in female rats. Furthermore, our results potentiate P4 supplementation in relieving the depressive-like symptomatology in OVX rats, most likely through fine-tuning of different neurotransmitter systems. In the context of an activated immune system, the application of E2 and/or P4 does not provide any advantageous effects on depressive-like behavior.",
journal = "Archives of Biological Sciences",
title = "Effects of Female Gonadal Hormones and Lps on Depressive-Like Behavior in Rats",
volume = "67",
number = "3",
pages = "1025-1032",
doi = "10.2298/ABS150130065M"
}

Mitić, M., Lukić, I., Božović, N., Đorđević, J. D.,& Adžić, M.. (2015). Effects of Female Gonadal Hormones and Lps on Depressive-Like Behavior in Rats. in Archives of Biological Sciences, 67(3), 1025-1032.
https://doi.org/10.2298/ABS150130065M

Mitić M, Lukić I, Božović N, Đorđević JD, Adžić M. Effects of Female Gonadal Hormones and Lps on Depressive-Like Behavior in Rats. in Archives of Biological Sciences. 2015;67(3):1025-1032.
doi:10.2298/ABS150130065M .

Mitić, Miloš, Lukić, Iva, Božović, Natalija, Đorđević, Jelena D., Adžić, Miroslav, "Effects of Female Gonadal Hormones and Lps on Depressive-Like Behavior in Rats" in Archives of Biological Sciences, 67, no. 3 (2015):1025-1032,
https://doi.org/10.2298/ABS150130065M . .

TY  - JOUR
AU  - Mitić, Miloš
AU  - Lukić, Iva
AU  - Božović, Natalija
AU  - Đorđević, Jelena D.
AU  - Adžić, Miroslav
PY  - 2015
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/367
AB  - A growing body of evidence indicates that mitogen-activated protein kinase (MAPK) participates in various stress-induced responses and is considered to be one of the pathophysiological mechanisms in depression. Surprisingly, the effect of antidepressants on MAPKs is almost unexplored, particularly from the perspective of sexes. The present study investigates the cytoplasm-nuclear distribution of MAPK family, c-Jun N-terminal kinases (JNKs) 1, 2 and 3; extracellular signal-regulated kinases (ERKs) 1 and 2; and p38 kinases, as well as their phosphoisoforms in the hippocampus of chronically stressed female and male rats and upon chronic fluoxetine treatment. Additionally, we analysed crosstalk between MAPK signalling and depressive-like behaviour which correlated with brain-derived neurotrophic factor (BDNF) expression. Our results emphasize a gender-specific and compartment-dependent response of MAPKs to stress and fluoxetine. In females, stress decreased pp38 and pJNK and induced cytosolic retention of pERKs which reduced all nuclear pMAPKs. These changes correlated with altered BDNF expression and behaviour. Similarly, in males, stress decreased pp38 but promoted nuclear translocation of pJNKs and pERKs. These stress alterations of pMAPKs in males were not associated with BDNF expression and depressive-like behaviour. Fluoxetine treatment in stressed females upregulated whole pMAPK signalling particularly those in nucleus which was followed with BDNF expression and normalization of behaviour. In stressed males, fluoxetine affected only cytosolic pJNKs, while nuclear pMAPK signalling and BDNF expression were unaffected even though fluoxetine normalized behaviour. Overall, our results suggest existence of gender-specific mechanism of fluoxetine on nuclear pMAPK/BDNF signalling and depressive-like behaviour and reinforce the antidepressant dogma that females and males respond differently to certain antidepressants.
T2  - Journal of Molecular Neuroscience
T1  - Fluoxetine Signature on Hippocampal MAPK Signalling in Sex-Dependent Manner
VL  - 55
IS  - 2
SP  - 335
EP  - 346
DO  - 10.1007/s12031-014-0328-1
ER  - 

@article{
author = "Mitić, Miloš and Lukić, Iva and Božović, Natalija and Đorđević, Jelena D. and Adžić, Miroslav",
year = "2015",
abstract = "A growing body of evidence indicates that mitogen-activated protein kinase (MAPK) participates in various stress-induced responses and is considered to be one of the pathophysiological mechanisms in depression. Surprisingly, the effect of antidepressants on MAPKs is almost unexplored, particularly from the perspective of sexes. The present study investigates the cytoplasm-nuclear distribution of MAPK family, c-Jun N-terminal kinases (JNKs) 1, 2 and 3; extracellular signal-regulated kinases (ERKs) 1 and 2; and p38 kinases, as well as their phosphoisoforms in the hippocampus of chronically stressed female and male rats and upon chronic fluoxetine treatment. Additionally, we analysed crosstalk between MAPK signalling and depressive-like behaviour which correlated with brain-derived neurotrophic factor (BDNF) expression. Our results emphasize a gender-specific and compartment-dependent response of MAPKs to stress and fluoxetine. In females, stress decreased pp38 and pJNK and induced cytosolic retention of pERKs which reduced all nuclear pMAPKs. These changes correlated with altered BDNF expression and behaviour. Similarly, in males, stress decreased pp38 but promoted nuclear translocation of pJNKs and pERKs. These stress alterations of pMAPKs in males were not associated with BDNF expression and depressive-like behaviour. Fluoxetine treatment in stressed females upregulated whole pMAPK signalling particularly those in nucleus which was followed with BDNF expression and normalization of behaviour. In stressed males, fluoxetine affected only cytosolic pJNKs, while nuclear pMAPK signalling and BDNF expression were unaffected even though fluoxetine normalized behaviour. Overall, our results suggest existence of gender-specific mechanism of fluoxetine on nuclear pMAPK/BDNF signalling and depressive-like behaviour and reinforce the antidepressant dogma that females and males respond differently to certain antidepressants.",
journal = "Journal of Molecular Neuroscience",
title = "Fluoxetine Signature on Hippocampal MAPK Signalling in Sex-Dependent Manner",
volume = "55",
number = "2",
pages = "335-346",
doi = "10.1007/s12031-014-0328-1"
}

Mitić, M., Lukić, I., Božović, N., Đorđević, J. D.,& Adžić, M.. (2015). Fluoxetine Signature on Hippocampal MAPK Signalling in Sex-Dependent Manner. in Journal of Molecular Neuroscience, 55(2), 335-346.
https://doi.org/10.1007/s12031-014-0328-1

Mitić M, Lukić I, Božović N, Đorđević JD, Adžić M. Fluoxetine Signature on Hippocampal MAPK Signalling in Sex-Dependent Manner. in Journal of Molecular Neuroscience. 2015;55(2):335-346.
doi:10.1007/s12031-014-0328-1 .

Mitić, Miloš, Lukić, Iva, Božović, Natalija, Đorđević, Jelena D., Adžić, Miroslav, "Fluoxetine Signature on Hippocampal MAPK Signalling in Sex-Dependent Manner" in Journal of Molecular Neuroscience, 55, no. 2 (2015):335-346,
https://doi.org/10.1007/s12031-014-0328-1 . .

TY  - JOUR
AU  - Lukić, Iva
AU  - Mitić, Miloš
AU  - Đorđević, Jelena D.
AU  - Tatalović, Nikola R.
AU  - Božović, Natalija
AU  - Soldatovic, Ivan
AU  - Mihaljević, Marina
AU  - Pavlović, Zorana
AU  - Radojčić, Marija
AU  - Marić, Nađa P.
AU  - Adžić, Miroslav
PY  - 2014
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/148
AB  - Background: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. Methods: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-kappa B (NF-kappa B), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). Results: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-kappa B in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-kappa B. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. Conclusion: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-kappa B) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients. (C) 2014 S. Karger AG, Basel
T2  - Neuropsychobiology
T1  - Lymphocyte Levels of Redox-Sensitive Transcription Factors and Antioxidative Enzymes as Indicators of Pro-Oxidative State in Depressive Patients
VL  - 70
IS  - 1
SP  - 1
EP  - 9
DO  - 10.1159/000362841
ER  - 

@article{
author = "Lukić, Iva and Mitić, Miloš and Đorđević, Jelena D. and Tatalović, Nikola R. and Božović, Natalija and Soldatovic, Ivan and Mihaljević, Marina and Pavlović, Zorana and Radojčić, Marija and Marić, Nađa P. and Adžić, Miroslav",
year = "2014",
abstract = "Background: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. Methods: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-kappa B (NF-kappa B), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). Results: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-kappa B in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-kappa B. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. Conclusion: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-kappa B) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients. (C) 2014 S. Karger AG, Basel",
journal = "Neuropsychobiology",
title = "Lymphocyte Levels of Redox-Sensitive Transcription Factors and Antioxidative Enzymes as Indicators of Pro-Oxidative State in Depressive Patients",
volume = "70",
number = "1",
pages = "1-9",
doi = "10.1159/000362841"
}

Lukić, I., Mitić, M., Đorđević, J. D., Tatalović, N. R., Božović, N., Soldatovic, I., Mihaljević, M., Pavlović, Z., Radojčić, M., Marić, N. P.,& Adžić, M.. (2014). Lymphocyte Levels of Redox-Sensitive Transcription Factors and Antioxidative Enzymes as Indicators of Pro-Oxidative State in Depressive Patients. in Neuropsychobiology, 70(1), 1-9.
https://doi.org/10.1159/000362841

Lukić I, Mitić M, Đorđević JD, Tatalović NR, Božović N, Soldatovic I, Mihaljević M, Pavlović Z, Radojčić M, Marić NP, Adžić M. Lymphocyte Levels of Redox-Sensitive Transcription Factors and Antioxidative Enzymes as Indicators of Pro-Oxidative State in Depressive Patients. in Neuropsychobiology. 2014;70(1):1-9.
doi:10.1159/000362841 .

Lukić, Iva, Mitić, Miloš, Đorđević, Jelena D., Tatalović, Nikola R., Božović, Natalija, Soldatovic, Ivan, Mihaljević, Marina, Pavlović, Zorana, Radojčić, Marija, Marić, Nađa P., Adžić, Miroslav, "Lymphocyte Levels of Redox-Sensitive Transcription Factors and Antioxidative Enzymes as Indicators of Pro-Oxidative State in Depressive Patients" in Neuropsychobiology, 70, no. 1 (2014):1-9,
https://doi.org/10.1159/000362841 . .