Todorović, Nevena

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orcid::0000-0003-2806-1991
  • Todorović, Nevena (9)
  • Todorović Vukotić, Nevena (1)
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Author's Bibliography

Antidepressants- and antipsychotics-induced hepatotoxicity

Todorović Vukotić, Nevena; Đorđević, Jelena; Pejić, Snežana; Đorđević, Neda O.; Pajović, Snežana B.

(2021)

TY  - JOUR
AU  - Todorović Vukotić, Nevena
AU  - Đorđević, Jelena
AU  - Pejić, Snežana
AU  - Đorđević, Neda O.
AU  - Pajović, Snežana B.
PY  - 2021
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9078
AB  - Drug-induced liver injury (DILI) is a serious health burden. It has diverse clinical presentations that can escalate to acute liver failure. The worldwide increase in the use of psychotropic drugs, their long-term use on a daily basis, common comorbidities of psychiatric and metabolic disorders, and polypharmacy in psychiatric patients increase the incidence of psychotropics-induced DILI. During the last 2 decades, hepatotoxicity of various antidepressants (ADs) and antipsychotics (APs) received much attention. Comprehensive review and discussion of accumulated literature data concerning this issue are performed in this study, as hepatotoxic effects of most commonly prescribed ADs and APs are classified, described, and discussed. The review focuses on ADs and APs characterized by the risk of causing liver damage and highlights the ones found to cause life-threatening or severe DILI cases. In parallel, an overview of hepatic oxidative stress, inflammation, and steatosis underlying DILI is provided, followed by extensive review and discussion of the pathophysiology of AD- and AP-induced DILI revealed in case reports, and animal and in vitro studies. The consequences of some ADs and APs ability to affect drug-metabolizing enzymes and therefore provoke drug–drug interactions are also addressed. Continuous collecting of data on drugs, mechanisms, and risk factors for DILI, as well as critical data reviewing, is crucial for easier DILI diagnosis and more efficient risk assessment of AD- and AP-induced DILI. Higher awareness of ADs and APs hepatotoxicity is the prerequisite for their safe use and optimal dosing. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
T2  - Archives of Toxicology
T1  - Antidepressants- and antipsychotics-induced hepatotoxicity
VL  - 95
IS  - 3
SP  - 767
EP  - 789
DO  - 10.1007/s00204-020-02963-4
ER  - 
@article{
author = "Todorović Vukotić, Nevena and Đorđević, Jelena and Pejić, Snežana and Đorđević, Neda O. and Pajović, Snežana B.",
year = "2021",
url = "https://vinar.vin.bg.ac.rs/handle/123456789/9078",
abstract = "Drug-induced liver injury (DILI) is a serious health burden. It has diverse clinical presentations that can escalate to acute liver failure. The worldwide increase in the use of psychotropic drugs, their long-term use on a daily basis, common comorbidities of psychiatric and metabolic disorders, and polypharmacy in psychiatric patients increase the incidence of psychotropics-induced DILI. During the last 2 decades, hepatotoxicity of various antidepressants (ADs) and antipsychotics (APs) received much attention. Comprehensive review and discussion of accumulated literature data concerning this issue are performed in this study, as hepatotoxic effects of most commonly prescribed ADs and APs are classified, described, and discussed. The review focuses on ADs and APs characterized by the risk of causing liver damage and highlights the ones found to cause life-threatening or severe DILI cases. In parallel, an overview of hepatic oxidative stress, inflammation, and steatosis underlying DILI is provided, followed by extensive review and discussion of the pathophysiology of AD- and AP-induced DILI revealed in case reports, and animal and in vitro studies. The consequences of some ADs and APs ability to affect drug-metabolizing enzymes and therefore provoke drug–drug interactions are also addressed. Continuous collecting of data on drugs, mechanisms, and risk factors for DILI, as well as critical data reviewing, is crucial for easier DILI diagnosis and more efficient risk assessment of AD- and AP-induced DILI. Higher awareness of ADs and APs hepatotoxicity is the prerequisite for their safe use and optimal dosing. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.",
journal = "Archives of Toxicology",
title = "Antidepressants- and antipsychotics-induced hepatotoxicity",
volume = "95",
number = "3",
pages = "767-789",
doi = "10.1007/s00204-020-02963-4"
}
Todorović Vukotić, N., Đorđević, J., Pejić, S., Đorđević, N. O.,& Pajović, S. B. (2021). Antidepressants- and antipsychotics-induced hepatotoxicity.
Archives of Toxicology, 95(3), 767-789.
https://doi.org/10.1007/s00204-020-02963-4
Todorović Vukotić N, Đorđević J, Pejić S, Đorđević NO, Pajović SB. Antidepressants- and antipsychotics-induced hepatotoxicity. Archives of Toxicology. 2021;95(3):767-789
Todorović Vukotić Nevena, Đorđević Jelena, Pejić Snežana, Đorđević Neda O., Pajović Snežana B., "Antidepressants- and antipsychotics-induced hepatotoxicity" Archives of Toxicology, 95, no. 3 (2021):767-789,
https://doi.org/10.1007/s00204-020-02963-4 .
1

Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats

Todorović, Nevena; Mićić, Bojana; Schwirtlich, Marija; Stevanović, Milena J.; Filipović, Dragana

(2019)

TY  - JOUR
AU  - Todorović, Nevena
AU  - Mićić, Bojana
AU  - Schwirtlich, Marija
AU  - Stevanović, Milena J.
AU  - Filipović, Dragana
PY  - 2019
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0306452218307322
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/7982
AB  - Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin-positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3-positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia. Also, we examined potential protective effects of antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) on the number of these cells in mPFC subregions, when applied parallel with CSIS in doses that correspond to therapeutically effective ones in patients. Immunofluorescence analysis revealed decreased number of PV+ cells in cingulate cortex area 1, prelimbic area (PrL), infralimbic area (IL) and dorsal peduncular cortex of the mPFC in isolated rats, which coincided with depressive- and anxiety-like behaviors. In addition, CSIS-induced increase in the number of CC3+ cells was detected in aforementioned subregions of mPFC. Treatments with either FLX or CLZ prevented behavioral changes, decrease in PV+ and increase in CC3+ cell numbers in PrL and IL subregions in isolated rats. These results indicate the importance of intact GABAergic signaling in these areas for resistance against CSIS-induced behavioral changes, as well as subregion-specific protective effects of FLX and CLZ in mPFC of CSIS rats. © 2018 IBRO
T2  - Neuroscience
T1  - Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats
VL  - 396
SP  - 24
EP  - 35
DO  - 10.1016/j.neuroscience.2018.11.008
ER  - 
@article{
author = "Todorović, Nevena and Mićić, Bojana and Schwirtlich, Marija and Stevanović, Milena J. and Filipović, Dragana",
year = "2019",
url = "https://linkinghub.elsevier.com/retrieve/pii/S0306452218307322, http://vinar.vin.bg.ac.rs/handle/123456789/7982",
abstract = "Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin-positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3-positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia. Also, we examined potential protective effects of antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) on the number of these cells in mPFC subregions, when applied parallel with CSIS in doses that correspond to therapeutically effective ones in patients. Immunofluorescence analysis revealed decreased number of PV+ cells in cingulate cortex area 1, prelimbic area (PrL), infralimbic area (IL) and dorsal peduncular cortex of the mPFC in isolated rats, which coincided with depressive- and anxiety-like behaviors. In addition, CSIS-induced increase in the number of CC3+ cells was detected in aforementioned subregions of mPFC. Treatments with either FLX or CLZ prevented behavioral changes, decrease in PV+ and increase in CC3+ cell numbers in PrL and IL subregions in isolated rats. These results indicate the importance of intact GABAergic signaling in these areas for resistance against CSIS-induced behavioral changes, as well as subregion-specific protective effects of FLX and CLZ in mPFC of CSIS rats. © 2018 IBRO",
journal = "Neuroscience",
title = "Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats",
volume = "396",
pages = "24-35",
doi = "10.1016/j.neuroscience.2018.11.008"
}
Todorović, N., Mićić, B., Schwirtlich, M., Stevanović, M. J.,& Filipović, D. (2019). Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats.
Neuroscience, 396, 24-35.
https://doi.org/10.1016/j.neuroscience.2018.11.008
Todorović N, Mićić B, Schwirtlich M, Stevanović MJ, Filipović D. Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats. Neuroscience. 2019;396:24-35
Todorović Nevena, Mićić Bojana, Schwirtlich Marija, Stevanović Milena J., Filipović Dragana, "Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats" Neuroscience, 396 (2019):24-35,
https://doi.org/10.1016/j.neuroscience.2018.11.008 .
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Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine

Đorđević, Neda O.; Todorović, Nevena; Novaković, Irena T.; Pezo, Lato; Pejin, Boris; Maraš, Vesna; Tešević, Vele V.; Pajović, Snežana B.

(2018)

TY  - JOUR
AU  - Đorđević, Neda O.
AU  - Todorović, Nevena
AU  - Novaković, Irena T.
AU  - Pezo, Lato
AU  - Pejin, Boris
AU  - Maraš, Vesna
AU  - Tešević, Vele V.
AU  - Pajović, Snežana B.
PY  - 2018
UR  - http://www.mdpi.com/1420-3049/23/8/1971
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/7858
AB  - Screens of antioxidant activity (AA) of various natural products have been a focus of the research community worldwide. This work aimed to differentiate selected samples of Merlot wines originated from Montenegro, with regard to phenolic profile and antioxidant capacity studied by survival rate, total sulfhydryl groups and activities of glutathione peroxidase (GPx), glutathione reductase and catalase in H2O2–stressed Saccharomyces cerevisiae cells. In this study, DPPH assay was also performed. Higher total phenolic content leads to an enhanced AA under both conditions. The same trend was observed for catechin and gallic acid, the most abundant phenolics in the examined wine samples. Finally, the findings of an Artificial Neural Network (ANN) model were in a good agreement (r2 = 0.978) with the experimental data. All tested samples exhibited a protective effect in H2O2–stressed yeast cells. Pre-treatment with examined wines increased survival in H2O2–stressed cells and shifted antioxidative defense towards GPx–mediated defense. Finally, sensitivity analysis of obtained ANN model highlights the complexity of the impact that variations in the concentrations of specific phenolic components have on the antioxidant defense system.
T2  - Molecules
T1  - Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine
VL  - 23
IS  - 8
SP  - 1971
DO  - 10.3390/molecules23081971
ER  - 
@article{
author = "Đorđević, Neda O. and Todorović, Nevena and Novaković, Irena T. and Pezo, Lato and Pejin, Boris and Maraš, Vesna and Tešević, Vele V. and Pajović, Snežana B.",
year = "2018",
url = "http://www.mdpi.com/1420-3049/23/8/1971, http://vinar.vin.bg.ac.rs/handle/123456789/7858",
abstract = "Screens of antioxidant activity (AA) of various natural products have been a focus of the research community worldwide. This work aimed to differentiate selected samples of Merlot wines originated from Montenegro, with regard to phenolic profile and antioxidant capacity studied by survival rate, total sulfhydryl groups and activities of glutathione peroxidase (GPx), glutathione reductase and catalase in H2O2–stressed Saccharomyces cerevisiae cells. In this study, DPPH assay was also performed. Higher total phenolic content leads to an enhanced AA under both conditions. The same trend was observed for catechin and gallic acid, the most abundant phenolics in the examined wine samples. Finally, the findings of an Artificial Neural Network (ANN) model were in a good agreement (r2 = 0.978) with the experimental data. All tested samples exhibited a protective effect in H2O2–stressed yeast cells. Pre-treatment with examined wines increased survival in H2O2–stressed cells and shifted antioxidative defense towards GPx–mediated defense. Finally, sensitivity analysis of obtained ANN model highlights the complexity of the impact that variations in the concentrations of specific phenolic components have on the antioxidant defense system.",
journal = "Molecules",
title = "Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine",
volume = "23",
number = "8",
pages = "1971",
doi = "10.3390/molecules23081971"
}
Đorđević, N. O., Todorović, N., Novaković, I. T., Pezo, L., Pejin, B., Maraš, V., Tešević, V. V.,& Pajović, S. B. (2018). Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine.
Molecules, 23(8), 1971.
https://doi.org/10.3390/molecules23081971
Đorđević NO, Todorović N, Novaković IT, Pezo L, Pejin B, Maraš V, Tešević VV, Pajović SB. Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine. Molecules. 2018;23(8):1971
Đorđević Neda O., Todorović Nevena, Novaković Irena T., Pezo Lato, Pejin Boris, Maraš Vesna, Tešević Vele V., Pajović Snežana B., "Antioxidant Activity of Selected Polyphenolics in Yeast Cells: The Case Study of Montenegrin Merlot Wine" Molecules, 23, no. 8 (2018):1971,
https://doi.org/10.3390/molecules23081971 .
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The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha

Todorović, Nevena; Filipović, Dragana

(2017)

TY  - JOUR
AU  - Todorović, Nevena
AU  - Filipović, Dragana
PY  - 2017
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/1875
AB  - Brain oxidative stress and neuroinflammation are implicated in psychiatric disorders. Thus, it is important to investigate the effects of individual psychotropic agents on antioxidative defense and proinflammatory mediators in brain regions associated with these disorders. Psychosocial stress is recognized as a threat to mental health, and the hippocampus is a primary target of stress-related damage. Chronic social isolation (CSIS) is a mild psychosocial stress used to model the pathophysiology of depression. We examined the antioxidative and anti-inflammatory potential of the antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) in the hippocampus in the CSIS model of depression. We measured the effects of FLX and CLZ on depressive- and anxiety-like behaviors in non-stressed rats and rats exposed to 21d of CSIS. We further evaluated the content of reduced glutathione (GSH), the protein expression and activity of the GSH-related enzymes, the subcellular localization of nuclear factor-kappa B (NF-kappa B)and protein levels of proinflammatory mediators cyclooxygenase-2 (COX-2), interleukin-lbeta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) in these groups of rats. CSIS resulted in an increase in depressive- and anxiety-like behaviors that corresponded with compromised glutathione peroxidase (GPx)-mediated antioxidative defense and increased TNF-alpha, but not with changes in NF-kappa B, IL-1 beta and COX-2 levels. FLX and CLZ, applied during CSIS, prevented the behavioral changes associated with CSIS, and inhibited the increase in TNF-alpha, but did not affect GPx-mediated antioxidative defense. Furthermore, both drugs decreased hippocampal GPx activity when applied to non-stressed rats. These results emphasize the significance of hippocampal TNF-alpha-mediated proinflammmatory signaling in the pathophysiology of depressive symptoms and the importance of the anti-inflammatory action of both FLX and CLZ in the prevention of these symptoms.
T2  - Pharmacology Biochemistry and Behavior
T1  - The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha
VL  - 163
SP  - 57
EP  - 65
DO  - 10.1016/j.pbb.2017.10.006
ER  - 
@article{
author = "Todorović, Nevena and Filipović, Dragana",
year = "2017",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/1875",
abstract = "Brain oxidative stress and neuroinflammation are implicated in psychiatric disorders. Thus, it is important to investigate the effects of individual psychotropic agents on antioxidative defense and proinflammatory mediators in brain regions associated with these disorders. Psychosocial stress is recognized as a threat to mental health, and the hippocampus is a primary target of stress-related damage. Chronic social isolation (CSIS) is a mild psychosocial stress used to model the pathophysiology of depression. We examined the antioxidative and anti-inflammatory potential of the antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) in the hippocampus in the CSIS model of depression. We measured the effects of FLX and CLZ on depressive- and anxiety-like behaviors in non-stressed rats and rats exposed to 21d of CSIS. We further evaluated the content of reduced glutathione (GSH), the protein expression and activity of the GSH-related enzymes, the subcellular localization of nuclear factor-kappa B (NF-kappa B)and protein levels of proinflammatory mediators cyclooxygenase-2 (COX-2), interleukin-lbeta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) in these groups of rats. CSIS resulted in an increase in depressive- and anxiety-like behaviors that corresponded with compromised glutathione peroxidase (GPx)-mediated antioxidative defense and increased TNF-alpha, but not with changes in NF-kappa B, IL-1 beta and COX-2 levels. FLX and CLZ, applied during CSIS, prevented the behavioral changes associated with CSIS, and inhibited the increase in TNF-alpha, but did not affect GPx-mediated antioxidative defense. Furthermore, both drugs decreased hippocampal GPx activity when applied to non-stressed rats. These results emphasize the significance of hippocampal TNF-alpha-mediated proinflammmatory signaling in the pathophysiology of depressive symptoms and the importance of the anti-inflammatory action of both FLX and CLZ in the prevention of these symptoms.",
journal = "Pharmacology Biochemistry and Behavior",
title = "The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha",
volume = "163",
pages = "57-65",
doi = "10.1016/j.pbb.2017.10.006"
}
Todorović, N.,& Filipović, D. (2017). The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha.
Pharmacology Biochemistry and Behavior, 163, 57-65.
https://doi.org/10.1016/j.pbb.2017.10.006
Todorović N, Filipović D. The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha. Pharmacology Biochemistry and Behavior. 2017;163:57-65
Todorović Nevena, Filipović Dragana, "The antidepressant- and anxiolytic-like effects of fluoxetine and clozapine in chronically isolated rats involve inhibition of hippocampal TNF-alpha" Pharmacology Biochemistry and Behavior, 163 (2017):57-65,
https://doi.org/10.1016/j.pbb.2017.10.006 .
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Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine

Todorović, Nevena; Filipović, Dragana

(2017)

TY  - JOUR
AU  - Todorović, Nevena
AU  - Filipović, Dragana
PY  - 2017
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/1613
AB  - Chronic psychosocial stress modulates brain antioxidant systems and causes neuroinflammation that plays a role in the pathophysiology of depression. Although the antidepressant fluoxetine (FLX) represents the first-line treatment for depression and the atypical antipsychotic clozapine (CLZ) is considered as a second-line treatment for psychotic disorders, the downstream mechanisms of action of these treatments, beyond serotonergic or dopaminergic signaling, remain elusive. We examined behavioral changes, glutathione (GSH)-dependent defense and levels of proinflammatory mediators in the prefrontal cortex (PFC) of adult male Wistar rats exposed to 21 days of chronic social isolation (CSIS). We also tested the ability of FLX (15 mg/kg/day) or CLZ (20 mg/kg/day), applied during CSIS, to prevent stress-induced changes. CSIS caused depressive-and anxiety-like behaviors, compromised GSH-dependent defense, and induced nuclear factor-kappa B (NF-kappa B) activation with a concomitant increase in cytosolic levels of proinflammatory mediators cyclooxigenase-2, interleukin-1beta and tumor necrosis factor-alpha in the PFC. NF-kappa B activation and proinflammatory response in the PFC were not found in CSIS rats treated with FLX or CLZ. In contrast, only FLX preserved GSH content in CSIS rats. CLZ not only failed to protect against CSIS-induced GSH depletion, but it diminished its levels when applied to non-stressed rats. In conclusion, prefrontal cortical GSH depletion and the proinflammatory response underlying depressive-and anxiety-like states induced by CSIS were prevented by FLX. The protective effect of CLZ, which was equally effective as FLX on the behavioral level, was limited to proinflammatory components. Hence, different mechanisms underlie the protective effects of these two drugs in CSIS rats. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
T2  - Neuroscience
T1  - Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine
VL  - 355
SP  - 49
EP  - 60
DO  - 10.1016/j.neuroscience.2017.04.044
ER  - 
@article{
author = "Todorović, Nevena and Filipović, Dragana",
year = "2017",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/1613",
abstract = "Chronic psychosocial stress modulates brain antioxidant systems and causes neuroinflammation that plays a role in the pathophysiology of depression. Although the antidepressant fluoxetine (FLX) represents the first-line treatment for depression and the atypical antipsychotic clozapine (CLZ) is considered as a second-line treatment for psychotic disorders, the downstream mechanisms of action of these treatments, beyond serotonergic or dopaminergic signaling, remain elusive. We examined behavioral changes, glutathione (GSH)-dependent defense and levels of proinflammatory mediators in the prefrontal cortex (PFC) of adult male Wistar rats exposed to 21 days of chronic social isolation (CSIS). We also tested the ability of FLX (15 mg/kg/day) or CLZ (20 mg/kg/day), applied during CSIS, to prevent stress-induced changes. CSIS caused depressive-and anxiety-like behaviors, compromised GSH-dependent defense, and induced nuclear factor-kappa B (NF-kappa B) activation with a concomitant increase in cytosolic levels of proinflammatory mediators cyclooxigenase-2, interleukin-1beta and tumor necrosis factor-alpha in the PFC. NF-kappa B activation and proinflammatory response in the PFC were not found in CSIS rats treated with FLX or CLZ. In contrast, only FLX preserved GSH content in CSIS rats. CLZ not only failed to protect against CSIS-induced GSH depletion, but it diminished its levels when applied to non-stressed rats. In conclusion, prefrontal cortical GSH depletion and the proinflammatory response underlying depressive-and anxiety-like states induced by CSIS were prevented by FLX. The protective effect of CLZ, which was equally effective as FLX on the behavioral level, was limited to proinflammatory components. Hence, different mechanisms underlie the protective effects of these two drugs in CSIS rats. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.",
journal = "Neuroscience",
title = "Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine",
volume = "355",
pages = "49-60",
doi = "10.1016/j.neuroscience.2017.04.044"
}
Todorović, N.,& Filipović, D. (2017). Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine.
Neuroscience, 355, 49-60.
https://doi.org/10.1016/j.neuroscience.2017.04.044
Todorović N, Filipović D. Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine. Neuroscience. 2017;355:49-60
Todorović Nevena, Filipović Dragana, "Prefrontal Cortical Glutathione-Dependent Defense and Proinflammatory Mediators in Chronically Isolated Rats: Modulation By Fluoxetine Or Clozapine" Neuroscience, 355 (2017):49-60,
https://doi.org/10.1016/j.neuroscience.2017.04.044 .
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Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms

Filipović, Dragana; Todorović, Nevena; Bernardi, Rick E.; Gass, Peter

(2017)

TY  - JOUR
AU  - Filipović, Dragana
AU  - Todorović, Nevena
AU  - Bernardi, Rick E.
AU  - Gass, Peter
PY  - 2017
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/1392
AB  - Various stressors may disrupt the redox homeostasis of an organism by causing oxidative and nitrosative stress that may activate stressor-specific pathways and provoke specific responses. Chronic social isolation (CSIS) represents a mild chronic stress that evokes a variety of neurobehavioral changes in rats similar to those observed in people with psychiatric disorders, including depression. Most rodent studies have focused on the effect of social isolation during weaning or adolescence, while its effect in adult rats has not been extensively examined. In this review, we discuss the current knowledge regarding the involvement of oxidative/nitrosative stress pathways in the prefrontal cortex and hippocampus of adult male rats exposed to CSIS, focusing on hypothalamic-pituitary-adrenocortical (HPA) axis activity, behavior parameters, antioxidative defense systems, stress signaling mediated by nuclear factor-kappa B (NF-kappa B), and mitochondria-related proapoptotic signaling. Although increased concentrations of corticosterone (CORT) have been shown to induce oxidative and nitrosative stress, we suggest a mechanism underlying the glucocorticoid paradox whereby a state of oxidative/nitrosative stress may exist under basal CORT levels. This review also highlights the differential susceptibility of prefrontal cortex and hippocampus to oxidative stress following CSIS and suggests a possible cellular pathway of stress tolerance that preserves the hippocampus from molecular damage and apoptosis. The differential regulation of the transcriptional factor NF-kappa B, and the enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) following CSIS may be one functional difference between the response of the prefrontal cortex and hippocampus, thus identifying potentially relevant targets for antidepressant treatment.
T2  - Brain Structure and Function
T1  - Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms
VL  - 222
IS  - 1
SP  - 1
EP  - 20
DO  - 10.1007/s00429-016-1218-9
ER  - 
@article{
author = "Filipović, Dragana and Todorović, Nevena and Bernardi, Rick E. and Gass, Peter",
year = "2017",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/1392",
abstract = "Various stressors may disrupt the redox homeostasis of an organism by causing oxidative and nitrosative stress that may activate stressor-specific pathways and provoke specific responses. Chronic social isolation (CSIS) represents a mild chronic stress that evokes a variety of neurobehavioral changes in rats similar to those observed in people with psychiatric disorders, including depression. Most rodent studies have focused on the effect of social isolation during weaning or adolescence, while its effect in adult rats has not been extensively examined. In this review, we discuss the current knowledge regarding the involvement of oxidative/nitrosative stress pathways in the prefrontal cortex and hippocampus of adult male rats exposed to CSIS, focusing on hypothalamic-pituitary-adrenocortical (HPA) axis activity, behavior parameters, antioxidative defense systems, stress signaling mediated by nuclear factor-kappa B (NF-kappa B), and mitochondria-related proapoptotic signaling. Although increased concentrations of corticosterone (CORT) have been shown to induce oxidative and nitrosative stress, we suggest a mechanism underlying the glucocorticoid paradox whereby a state of oxidative/nitrosative stress may exist under basal CORT levels. This review also highlights the differential susceptibility of prefrontal cortex and hippocampus to oxidative stress following CSIS and suggests a possible cellular pathway of stress tolerance that preserves the hippocampus from molecular damage and apoptosis. The differential regulation of the transcriptional factor NF-kappa B, and the enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) following CSIS may be one functional difference between the response of the prefrontal cortex and hippocampus, thus identifying potentially relevant targets for antidepressant treatment.",
journal = "Brain Structure and Function",
title = "Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms",
volume = "222",
number = "1",
pages = "1-20",
doi = "10.1007/s00429-016-1218-9"
}
Filipović, D., Todorović, N., Bernardi, R. E.,& Gass, P. (2017). Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms.
Brain Structure and Function, 222(1), 1-20.
https://doi.org/10.1007/s00429-016-1218-9
Filipović D, Todorović N, Bernardi RE, Gass P. Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms. Brain Structure and Function. 2017;222(1):1-20
Filipović Dragana, Todorović Nevena, Bernardi Rick E., Gass Peter, "Oxidative and nitrosative stress pathways in the brain of socially isolated adult male rats demonstrating depressive- and anxiety-like symptoms" Brain Structure and Function, 222, no. 1 (2017):1-20,
https://doi.org/10.1007/s00429-016-1218-9 .
1
63
53
60

Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats

Todorović, Nevena; Tomanovic, Nada; Gass, Peter; Filipović, Dragana

(2016)

TY  - JOUR
AU  - Todorović, Nevena
AU  - Tomanovic, Nada
AU  - Gass, Peter
AU  - Filipović, Dragana
PY  - 2016
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/883
AB  - Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5 mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6 weeks of chronic social isolation (CSIS), which causes depressive-and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-kappa B (NF-kappa B), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-kappa B nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-kappa B activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle-or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation. (C) 2015 Elsevier B.V. All rights reserved.
T2  - European Journal of Pharmaceutical Sciences
T1  - Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats
VL  - 81
SP  - 94
EP  - 102
DO  - 10.1016/j.ejps.2015.10.010
ER  - 
@article{
author = "Todorović, Nevena and Tomanovic, Nada and Gass, Peter and Filipović, Dragana",
year = "2016",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/883",
abstract = "Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5 mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6 weeks of chronic social isolation (CSIS), which causes depressive-and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-kappa B (NF-kappa B), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-kappa B nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-kappa B activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle-or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation. (C) 2015 Elsevier B.V. All rights reserved.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats",
volume = "81",
pages = "94-102",
doi = "10.1016/j.ejps.2015.10.010"
}
Todorović, N., Tomanovic, N., Gass, P.,& Filipović, D. (2016). Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats.
European Journal of Pharmaceutical Sciences, 81, 94-102.
https://doi.org/10.1016/j.ejps.2015.10.010
Todorović N, Tomanovic N, Gass P, Filipović D. Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats. European Journal of Pharmaceutical Sciences. 2016;81:94-102
Todorović Nevena, Tomanovic Nada, Gass Peter, Filipović Dragana, "Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats" European Journal of Pharmaceutical Sciences, 81 (2016):94-102,
https://doi.org/10.1016/j.ejps.2015.10.010 .
10
21
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19

Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice

Petrusic, Vladimir; Todorović, Nevena; Zivkovic, Irena; Dimitrijevic, Rajna; Muhandes, Lina; Rajnpreht, Irena; Dimitrijevic, Ljiljana

(2015)

TY  - JOUR
AU  - Petrusic, Vladimir
AU  - Todorović, Nevena
AU  - Zivkovic, Irena
AU  - Dimitrijevic, Rajna
AU  - Muhandes, Lina
AU  - Rajnpreht, Irena
AU  - Dimitrijevic, Ljiljana
PY  - 2015
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/465
AB  - Recent data concerning antiphospholipid syndrome (APS) induction have shown that beta(2)-glycoprotein I (beta(2)GPI) binds lipopolysaccharide (LPS), which results in conformational changes, exposition of a cryptic epitope and possible pathological anti-beta(2)GPI antibody production. In order to investigate the effects of LPS on the induction of APS-related pathology, we performed hyperimmunization of BALB/c and C57BL/6 mice with LPS, alone or in combination with tetanus toxoid (TTd), a protein structurally similar to beta(2)GPI. We report that, although high affinity pathological anti-beta(2)GPI antibodies were produced in all groups of animals, the reproductive pathology was recorded only in mice that received both LPS and TTd, implying on the important roles of both infections and molecular mimicry in APS pathogenesis. Moreover, APS-related reproductive pathology was more pronounced in BALB/c (lowered fertility and fecundity) than C57BL/6 mice (lowered fecundity), which correlated well with the disruption in natural antibody network observed in BALB/c mouse strain.
T2  - Autoimmunity
T1  - Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice
VL  - 48
IS  - 2
SP  - 87
EP  - 99
DO  - 10.3109/08916934.2014.961061
ER  - 
@article{
author = "Petrusic, Vladimir and Todorović, Nevena and Zivkovic, Irena and Dimitrijevic, Rajna and Muhandes, Lina and Rajnpreht, Irena and Dimitrijevic, Ljiljana",
year = "2015",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/465",
abstract = "Recent data concerning antiphospholipid syndrome (APS) induction have shown that beta(2)-glycoprotein I (beta(2)GPI) binds lipopolysaccharide (LPS), which results in conformational changes, exposition of a cryptic epitope and possible pathological anti-beta(2)GPI antibody production. In order to investigate the effects of LPS on the induction of APS-related pathology, we performed hyperimmunization of BALB/c and C57BL/6 mice with LPS, alone or in combination with tetanus toxoid (TTd), a protein structurally similar to beta(2)GPI. We report that, although high affinity pathological anti-beta(2)GPI antibodies were produced in all groups of animals, the reproductive pathology was recorded only in mice that received both LPS and TTd, implying on the important roles of both infections and molecular mimicry in APS pathogenesis. Moreover, APS-related reproductive pathology was more pronounced in BALB/c (lowered fertility and fecundity) than C57BL/6 mice (lowered fecundity), which correlated well with the disruption in natural antibody network observed in BALB/c mouse strain.",
journal = "Autoimmunity",
title = "Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice",
volume = "48",
number = "2",
pages = "87-99",
doi = "10.3109/08916934.2014.961061"
}
Petrusic, V., Todorović, N., Zivkovic, I., Dimitrijevic, R., Muhandes, L., Rajnpreht, I.,& Dimitrijevic, L. (2015). Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice.
Autoimmunity, 48(2), 87-99.
https://doi.org/10.3109/08916934.2014.961061
Petrusic V, Todorović N, Zivkovic I, Dimitrijevic R, Muhandes L, Rajnpreht I, Dimitrijevic L. Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice. Autoimmunity. 2015;48(2):87-99
Petrusic Vladimir, Todorović Nevena, Zivkovic Irena, Dimitrijevic Rajna, Muhandes Lina, Rajnpreht Irena, Dimitrijevic Ljiljana, "Autoantibody response and pregnancy-related pathology induced by combined LPS and tetanus toxoid hyperimmunization in BALB/c and C57BL/6 mice" Autoimmunity, 48, no. 2 (2015):87-99,
https://doi.org/10.3109/08916934.2014.961061 .
1
5
4
4

Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress

Martinović, Jelena; Todorović, Nevena; Bošković, Maja; Pajović, Snežana B.; Demajo, Miroslav; Filipović, Dragana

(2014)

TY  - JOUR
AU  - Martinović, Jelena
AU  - Todorović, Nevena
AU  - Bošković, Maja
AU  - Pajović, Snežana B.
AU  - Demajo, Miroslav
AU  - Filipović, Dragana
PY  - 2014
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/6058
AB  - Chronic oxidative stress plays an important role in depression. The aim of present study was to examine the stress-induced changes in serum corticosterone (CORT) levels, cytosolic protein carbonyl groups, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) and total superoxide dismutase (SOD) activity in the prefrontal cortex versus hippocampus of male Wistar rats exposed to acute (2 h of immobilization or cold), chronic (21d of social isolation) stress, and their combination (chronic + acute stress). The subcellular distribution of nuclear factor-kappa B (NF-kappa B) and cytosolic cyclooxygenase 2 (COX-2) protein expressions were also examined. Depressive- and anxiety-like behaviors were assessed via the forced swim, sucrose preference, and marble burying tests in chronically isolated rats. Although both acute stressors resulted in elevated CORT, increased MDA in the prefrontal cortex and NF-kappa B activation accompanied by increased NO in the hippocampus were detected only following acute cold stress. Chronic isolation resulted in no change in CORT levels, but disabled appropriate response to novel acute stress and led to depressive- and anxiety-like behaviors. Increased oxidative/nitrosative stress markers, likely by NF-kappa B nuclear translocation and concomitant COX-2 upregulation, associated with decreased SOD activity and GSH levels, suggested the existence of oxidative stress in the prefrontal cortex. In contrast, hippocampus was less susceptible to oxidative damage showing only increase in protein carbonyl groups and depleted GSH. Taken together, the prefrontal cortex seems to be more sensitive to oxidative stress than the hippocampus following chronic isolation stress, which may be relevant for further research related to stress-induced depressive-like behavior.
T2  - Molecular and Cellular Biochemistry
T1  - Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress
VL  - 393
IS  - 1-2
SP  - 43
EP  - 57
DO  - 10.1007/s11010-014-2045-z
ER  - 
@article{
author = "Martinović, Jelena and Todorović, Nevena and Bošković, Maja and Pajović, Snežana B. and Demajo, Miroslav and Filipović, Dragana",
year = "2014",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/6058",
abstract = "Chronic oxidative stress plays an important role in depression. The aim of present study was to examine the stress-induced changes in serum corticosterone (CORT) levels, cytosolic protein carbonyl groups, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) and total superoxide dismutase (SOD) activity in the prefrontal cortex versus hippocampus of male Wistar rats exposed to acute (2 h of immobilization or cold), chronic (21d of social isolation) stress, and their combination (chronic + acute stress). The subcellular distribution of nuclear factor-kappa B (NF-kappa B) and cytosolic cyclooxygenase 2 (COX-2) protein expressions were also examined. Depressive- and anxiety-like behaviors were assessed via the forced swim, sucrose preference, and marble burying tests in chronically isolated rats. Although both acute stressors resulted in elevated CORT, increased MDA in the prefrontal cortex and NF-kappa B activation accompanied by increased NO in the hippocampus were detected only following acute cold stress. Chronic isolation resulted in no change in CORT levels, but disabled appropriate response to novel acute stress and led to depressive- and anxiety-like behaviors. Increased oxidative/nitrosative stress markers, likely by NF-kappa B nuclear translocation and concomitant COX-2 upregulation, associated with decreased SOD activity and GSH levels, suggested the existence of oxidative stress in the prefrontal cortex. In contrast, hippocampus was less susceptible to oxidative damage showing only increase in protein carbonyl groups and depleted GSH. Taken together, the prefrontal cortex seems to be more sensitive to oxidative stress than the hippocampus following chronic isolation stress, which may be relevant for further research related to stress-induced depressive-like behavior.",
journal = "Molecular and Cellular Biochemistry",
title = "Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress",
volume = "393",
number = "1-2",
pages = "43-57",
doi = "10.1007/s11010-014-2045-z"
}
Martinović, J., Todorović, N., Bošković, M., Pajović, S. B., Demajo, M.,& Filipović, D. (2014). Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress.
Molecular and Cellular Biochemistry, 393(1-2), 43-57.
https://doi.org/10.1007/s11010-014-2045-z
Martinović J, Todorović N, Bošković M, Pajović SB, Demajo M, Filipović D. Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress. Molecular and Cellular Biochemistry. 2014;393(1-2):43-57
Martinović Jelena, Todorović Nevena, Bošković Maja, Pajović Snežana B., Demajo Miroslav, Filipović Dragana, "Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress" Molecular and Cellular Biochemistry, 393, no. 1-2 (2014):43-57,
https://doi.org/10.1007/s11010-014-2045-z .
72
66
70

Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study

Martinović, Jelena; Todorović, Nevena; Tomanovic, Nada; Bošković, Maja; Djordjevic, Snezana; Lazarević-Pašti, Tamara; Bernardi, Rick E.; Djurdjevic, Aleksandra; Filipović, Dragana

(2014)

TY  - JOUR
AU  - Martinović, Jelena
AU  - Todorović, Nevena
AU  - Tomanovic, Nada
AU  - Bošković, Maja
AU  - Djordjevic, Snezana
AU  - Lazarević-Pašti, Tamara
AU  - Bernardi, Rick E.
AU  - Djurdjevic, Aleksandra
AU  - Filipović, Dragana
PY  - 2014
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/6043
AB  - Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15 mg/kg/day) or clozapine (20 mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21 days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-kappa B (NF-kappa B), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-kappa B activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. (C) 2014 Elsevier B.V. All rights reserved.
T2  - European Journal of Pharmaceutical Sciences
T1  - Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study
VL  - 59
SP  - 20
EP  - 30
DO  - 10.1016/j.ejps.2014.04.010
ER  - 
@article{
author = "Martinović, Jelena and Todorović, Nevena and Tomanovic, Nada and Bošković, Maja and Djordjevic, Snezana and Lazarević-Pašti, Tamara and Bernardi, Rick E. and Djurdjevic, Aleksandra and Filipović, Dragana",
year = "2014",
url = "http://vinar.vin.bg.ac.rs/handle/123456789/6043",
abstract = "Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15 mg/kg/day) or clozapine (20 mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21 days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-kappa B (NF-kappa B), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-kappa B activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. (C) 2014 Elsevier B.V. All rights reserved.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study",
volume = "59",
pages = "20-30",
doi = "10.1016/j.ejps.2014.04.010"
}
Martinović, J., Todorović, N., Tomanovic, N., Bošković, M., Djordjevic, S., Lazarević-Pašti, T., Bernardi, R. E., Djurdjevic, A.,& Filipović, D. (2014). Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study.
European Journal of Pharmaceutical Sciences, 59, 20-30.
https://doi.org/10.1016/j.ejps.2014.04.010
Martinović J, Todorović N, Tomanovic N, Bošković M, Djordjevic S, Lazarević-Pašti T, Bernardi RE, Djurdjevic A, Filipović D. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study. European Journal of Pharmaceutical Sciences. 2014;59:20-30
Martinović Jelena, Todorović Nevena, Tomanovic Nada, Bošković Maja, Djordjevic Snezana, Lazarević-Pašti Tamara, Bernardi Rick E., Djurdjevic Aleksandra, Filipović Dragana, "Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study" European Journal of Pharmaceutical Sciences, 59 (2014):20-30,
https://doi.org/10.1016/j.ejps.2014.04.010 .
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