TY  - JOUR
AU  - Virijević, Kristina
AU  - Spasojević, Nataša
AU  - Stefanović, Bojana
AU  - Ferizović, Harisa
AU  - Janković, Milica
AU  - Vasiljević, Perica
AU  - Dronjak, Slađana
PY  - 2024
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12934
AB  - Wistar-Kyoto (WKY) rats subjected to chronic mild stress (CMS) represent a valid model of treatment-resistant depression (TRD). Considering that depression is more prevalent in women than in men, in the present study, female rats were used. We investigated the effect of CMS on behavior and different factors involved in neuroinflammatory processes and neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC) of WKY female rats. The results show that unstressed WKY females exhibited hypolocomotion, decreased exploratory behavior, and an increase in the total grooming time. After exposure to CMS, WKY females displayed intensified grooming. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed signaling and inflammatory pathways in the hippocampus and mPFC. The findings indicate reduced BDNF and elevated levels levels of IL-1β in both brain structures and NLRP3 in the mPFC of unstressed WKY female rats. WKY rats subjected to CMS showed a further decrease in BDNF levels and increased IL-1β and NLRP3 in these brain structures. WKY showed reduced pERK1/2 and increased pp38 levels in both brain structures, while CMS revealed a further increase of pp38 in WKY in these brain structures. Expressions of p110β and pAKT were decreased in the hippocampus and mPFC of WKY rats. The CMS further suppressed p110 and the downstream AKT phosphorylation in the hippocampus, but did not affect the p110 and pAKT in the mPFC. Our findings indicate behavioral and molecular differences in genetically vulnerable WKY female rats and in their response to CMS that may be involved in TRD.
T2  - Neuroscience Letters
T1  - Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats
VL  - 825
SP  - 137709
DO  - 10.1016/j.neulet.2024.137709
ER  - 

@article{
author = "Virijević, Kristina and Spasojević, Nataša and Stefanović, Bojana and Ferizović, Harisa and Janković, Milica and Vasiljević, Perica and Dronjak, Slađana",
year = "2024",
abstract = "Wistar-Kyoto (WKY) rats subjected to chronic mild stress (CMS) represent a valid model of treatment-resistant depression (TRD). Considering that depression is more prevalent in women than in men, in the present study, female rats were used. We investigated the effect of CMS on behavior and different factors involved in neuroinflammatory processes and neuroplasticity in the hippocampus and medial prefrontal cortex (mPFC) of WKY female rats. The results show that unstressed WKY females exhibited hypolocomotion, decreased exploratory behavior, and an increase in the total grooming time. After exposure to CMS, WKY females displayed intensified grooming. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed signaling and inflammatory pathways in the hippocampus and mPFC. The findings indicate reduced BDNF and elevated levels levels of IL-1β in both brain structures and NLRP3 in the mPFC of unstressed WKY female rats. WKY rats subjected to CMS showed a further decrease in BDNF levels and increased IL-1β and NLRP3 in these brain structures. WKY showed reduced pERK1/2 and increased pp38 levels in both brain structures, while CMS revealed a further increase of pp38 in WKY in these brain structures. Expressions of p110β and pAKT were decreased in the hippocampus and mPFC of WKY rats. The CMS further suppressed p110 and the downstream AKT phosphorylation in the hippocampus, but did not affect the p110 and pAKT in the mPFC. Our findings indicate behavioral and molecular differences in genetically vulnerable WKY female rats and in their response to CMS that may be involved in TRD.",
journal = "Neuroscience Letters",
title = "Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats",
volume = "825",
pages = "137709",
doi = "10.1016/j.neulet.2024.137709"
}

Virijević, K., Spasojević, N., Stefanović, B., Ferizović, H., Janković, M., Vasiljević, P.,& Dronjak, S.. (2024). Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats. in Neuroscience Letters, 825, 137709.
https://doi.org/10.1016/j.neulet.2024.137709

Virijević K, Spasojević N, Stefanović B, Ferizović H, Janković M, Vasiljević P, Dronjak S. Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats. in Neuroscience Letters. 2024;825:137709.
doi:10.1016/j.neulet.2024.137709 .

Virijević, Kristina, Spasojević, Nataša, Stefanović, Bojana, Ferizović, Harisa, Janković, Milica, Vasiljević, Perica, Dronjak, Slađana, "Chronic mild stress-induced dysregulation of MAPK and PI3K/AKT signaling in the hippocampus and medial prefrontal cortex of WKY female rats" in Neuroscience Letters, 825 (2024):137709,
https://doi.org/10.1016/j.neulet.2024.137709 . .

TY  - CONF
AU  - Janković, Milica
AU  - Ferizović, Harisa
AU  - Spasojević, Nataša
AU  - Stefanović, Bojana
AU  - Virijević, Kristina
AU  - Dronjak, Slađana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11059
AB  - Modulating the endocannabinoid system is emerging as a promising approach for treating various inflammatory, neurodegenerative, and psychiatric disorders. Major depressive disorder is a prevalent cause of disability worldwide, affecting up to 6% of the population and posing significant health and economic challenges. Since the existing antidepressant treatments are often insufficient, the endocannabinoid system presents an attractive target for potential therapies. To explore this possibility, two-month-old Wistar rats of both sexes were subjected to chronic unpredictable stress (CUS) for six weeks. During the last two weeks of stress protocol rats were injected with either a fatty acid amide hydrolase inhibitor, URB597 (i.p. 0.3 mg/kg), or a vehicle. At the end of the sixth week sucrose intake test was used to assess depressive-like behavior. After sacrificing the animals, Western blot analysis was used to determine the levels of brain-derived neurotrophic factor (BDNF) protein and levels of pro-inflammatory cytokine IL-1β in medial prefrontal cortex. The CUS exposure induced anhedonia in both female and male rats, and URB597 treatment alleviated these symptoms. Moreover, CUS increased the levels of IL1-β in the mPFC of both sexes. Stressed animals that have received URB597 had decreased levels of IL1-β structures compared to the animals receiving only vehicle. CUSexposed male and female rats also had lower levels of BDNF in the mPFC, but URB597 restored BDNF levels in female rats to those observed in control animals. Taken together, these findings suggest that URB597 may have antidepressant effects through reducing neuroinflammation and restoring BDNF levels in mPFC.
PB  - Belgrade : Serbian Neuroscience Society
C3  - 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
T1  - Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats
SP  - 118
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11059
ER  - 

@conference{
author = "Janković, Milica and Ferizović, Harisa and Spasojević, Nataša and Stefanović, Bojana and Virijević, Kristina and Dronjak, Slađana",
year = "2023",
abstract = "Modulating the endocannabinoid system is emerging as a promising approach for treating various inflammatory, neurodegenerative, and psychiatric disorders. Major depressive disorder is a prevalent cause of disability worldwide, affecting up to 6% of the population and posing significant health and economic challenges. Since the existing antidepressant treatments are often insufficient, the endocannabinoid system presents an attractive target for potential therapies. To explore this possibility, two-month-old Wistar rats of both sexes were subjected to chronic unpredictable stress (CUS) for six weeks. During the last two weeks of stress protocol rats were injected with either a fatty acid amide hydrolase inhibitor, URB597 (i.p. 0.3 mg/kg), or a vehicle. At the end of the sixth week sucrose intake test was used to assess depressive-like behavior. After sacrificing the animals, Western blot analysis was used to determine the levels of brain-derived neurotrophic factor (BDNF) protein and levels of pro-inflammatory cytokine IL-1β in medial prefrontal cortex. The CUS exposure induced anhedonia in both female and male rats, and URB597 treatment alleviated these symptoms. Moreover, CUS increased the levels of IL1-β in the mPFC of both sexes. Stressed animals that have received URB597 had decreased levels of IL1-β structures compared to the animals receiving only vehicle. CUSexposed male and female rats also had lower levels of BDNF in the mPFC, but URB597 restored BDNF levels in female rats to those observed in control animals. Taken together, these findings suggest that URB597 may have antidepressant effects through reducing neuroinflammation and restoring BDNF levels in mPFC.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade",
title = "Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats",
pages = "118",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11059"
}

Janković, M., Ferizović, H., Spasojević, N., Stefanović, B., Virijević, K.,& Dronjak, S.. (2023). Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neuroscience Society., 118.
https://hdl.handle.net/21.15107/rcub_vinar_11059

Janković M, Ferizović H, Spasojević N, Stefanović B, Virijević K, Dronjak S. Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:118.
https://hdl.handle.net/21.15107/rcub_vinar_11059 .

Janković, Milica, Ferizović, Harisa, Spasojević, Nataša, Stefanović, Bojana, Virijević, Kristina, Dronjak, Slađana, "Fatty acid amide hydrolase inhibitor URB597 shows antidepressant effects through reduction of neuroinflammation and restoration of BDNF levels in mPFC of chronically stressed rats" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):118,
https://hdl.handle.net/21.15107/rcub_vinar_11059 .

TY  - CONF
AU  - Virijević, Kristina
AU  - Spasojević, Nataša
AU  - Stefanović, Bojana
AU  - Ferizović, Harisa
AU  - Janković, Milica
AU  - Dronjak, Slađana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11053
AB  - Stress is a major precipitant of depression, the hippocampus (HPC) and prefrontal cortex (PFC) is the main structures affected by depressive disorders. Women are twice more likely to experience depression than men. The WKY rat strain has long been established as a model of depression. Initially bred from the Wistar (WI) rat as the control strain for the spontaneously hypertensive rat, WKY rats demonstrate an exaggerated stress response compared to other strains. WKY strain fails to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) and is considered to be nonresponsive to antidepressant drugs. MAPK signaling pathway was most closely related to depression and antidepressant treatment. In the present study, we have examined the effects of CMS on behavior and p38 MAPK signaling in the hippocampus and the medial prefrontal cortex (mPFC) of female WKY rats. We used two very different behavioral tests: forced swim test (FST) and open field test (OFT). WKY unstressed controls exhibited increased immobility duration in the forced swim test and decreased activity in the open-field test compared to unstressed WI rats, while CMS did not further influence behavior. WKY showed increased expression of the p38 only in HPC and further exposure of WKY rats to CMS induces sustained-activation of p38 MAPK in this brain area. The present study demonstrated the brain region-specific protein signatures in the female WKY model with endogenous depression, providing novel insights into the pathogenesis of depression.
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  - Chronic mild stress induces sustained-activation of p38 MAPK signaling in the female WKY rats with endogenous depression
SP  - 84
UR  - https://hdl.handle.net/21.15107/rcub_vinar_11053
ER  - 

@conference{
author = "Virijević, Kristina and Spasojević, Nataša and Stefanović, Bojana and Ferizović, Harisa and Janković, Milica and Dronjak, Slađana",
year = "2023",
abstract = "Stress is a major precipitant of depression, the hippocampus (HPC) and prefrontal cortex (PFC) is the main structures affected by depressive disorders. Women are twice more likely to experience depression than men. The WKY rat strain has long been established as a model of depression. Initially bred from the Wistar (WI) rat as the control strain for the spontaneously hypertensive rat, WKY rats demonstrate an exaggerated stress response compared to other strains. WKY strain fails to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) and is considered to be nonresponsive to antidepressant drugs. MAPK signaling pathway was most closely related to depression and antidepressant treatment. In the present study, we have examined the effects of CMS on behavior and p38 MAPK signaling in the hippocampus and the medial prefrontal cortex (mPFC) of female WKY rats. We used two very different behavioral tests: forced swim test (FST) and open field test (OFT). WKY unstressed controls exhibited increased immobility duration in the forced swim test and decreased activity in the open-field test compared to unstressed WI rats, while CMS did not further influence behavior. WKY showed increased expression of the p38 only in HPC and further exposure of WKY rats to CMS induces sustained-activation of p38 MAPK in this brain area. The present study demonstrated the brain region-specific protein signatures in the female WKY model with endogenous depression, providing novel insights into the pathogenesis of depression.",
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 = "Chronic mild stress induces sustained-activation of p38 MAPK signaling in the female WKY rats with endogenous depression",
pages = "84",
url = "https://hdl.handle.net/21.15107/rcub_vinar_11053"
}

Virijević, K., Spasojević, N., Stefanović, B., Ferizović, H., Janković, M.,& Dronjak, S.. (2023). Chronic mild stress induces sustained-activation of p38 MAPK signaling in the female WKY rats with endogenous depression. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade
Belgrade : Serbian Neurocardiological Society., 84.
https://hdl.handle.net/21.15107/rcub_vinar_11053

Virijević K, Spasojević N, Stefanović B, Ferizović H, Janković M, Dronjak S. Chronic mild stress induces sustained-activation of p38 MAPK signaling in the female WKY rats with endogenous depression. in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade. 2023;:84.
https://hdl.handle.net/21.15107/rcub_vinar_11053 .

Virijević, Kristina, Spasojević, Nataša, Stefanović, Bojana, Ferizović, Harisa, Janković, Milica, Dronjak, Slađana, "Chronic mild stress induces sustained-activation of p38 MAPK signaling in the female WKY rats with endogenous depression" in 8th Congress of Serbian neuroscience society with international participation : the book of abstracts; 31 May – 2 June; Belgrade (2023):84,
https://hdl.handle.net/21.15107/rcub_vinar_11053 .

TY  - CONF
AU  - Virijević, Kristina
AU  - Spasojević, Nataša
AU  - Stefanović, Bojana
AU  - Ferizović, Harisa
AU  - Janković, Milica
AU  - Dronjak, Slađana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12630
AB  - Background: The neurobiology underlying depression has not yet been fully identified, but is thought to result from molecular and cellular abnormalities that interact with genetic and environmental factors. Depression is twice as prevalent in women as in men, however, females remain underrepresented in preclinical research. In addition to the neurotransmission theory of depression, the inflammatory processes and the disrupted signaling pathways also play a crucial role in the pathophysiology of depression. The WKY rat strain has long been established as a model of depression. These rats demonstrate an exaggerated response to stress compared to other strains. WKY strain fail to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) and considered to be nonresponsive to antidepressant drugs. The hippocampus and the medial prefrontal cortex (mPFC) are thought to be an important regions for depression. Brain-derived neurotrophic factor (BDNF) play a vital role in the pathophysiology of depression. BDNF-stimulated signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)–/serine threonine kinase (Akt), also implicated in depression and treatment respons. In the present study, we have examined the effects of CMS on behavior and BDNF and PI3K/Akt signaling in the hippocampus and mPFC of female WKY rats.

Method: In the experiment, we used three months old Wistar (WI) and WKY female rats. Animals were divided in two groups: control and animals exposed to CMS for 6 weeks. On the last day of stress procedure, animals were tested in elevated plus maze to determine the levels of anxiety. Animals were then sacrificed and hippocampus and mPFC were isolated. Levels of BDNF and pAkt were determined by Western blot method. Data were analyzed using the two way ANOVA and Tuckey’s post-hoc test.

Results: WKY rats showed significantly decreased number of rearings (by 70%, p<0.01),decreased number of total arm entries (by 21%, p<0.05) and the time spent in the open arms (by 73%, p<0.001) of the elevated plus-maze compared to WI control group. WKY females had a significantly lower level of BDNF in the hippocampus (by 12%, p<0.05) and mPFC (by 16%, p<0.05) and pAkt (by 14%, p<0.01) only in mPFC as compared to the WI female rats. Exposure of WKY females to CMS enhanced an anxiety-like behavior and hypolomotion (decrease in number of rearings by 31%, p<0.05, number of total arm entries by 89%, p<0.001, and timevspent in the open arms by 92%, p<0.001), further down-expression of BDNF in both brain areas (in PFC: by 15%, p<0.001; in hippocampus: by 7%, p<0.05) and Akt phosphorylation in the mPFC (by 17%, p<0.05) as well as a decreased pAkt in the hippocampus (by 36%, p<0.001).

Conclusions: The difference in the balance of BDNF and PI3K/Akt signaling pathways may be relevant to the resistance of WKY rats to antidepressant drug treatment and may be useful for developing new targets for depression treatment, especially in females.
C3  - Neuroscience Applied
T1  - Dysregulation of BDNF and PI3K/Akt signaling in the brain of female Wistar-Kyoto rats exposed to chronic mild stress
VL  - 2
IS  - Supplement 2
SP  - 102596
DO  - 10.1016/j.nsa.2023.102596
ER  - 

@conference{
author = "Virijević, Kristina and Spasojević, Nataša and Stefanović, Bojana and Ferizović, Harisa and Janković, Milica and Dronjak, Slađana",
year = "2023",
abstract = "Background: The neurobiology underlying depression has not yet been fully identified, but is thought to result from molecular and cellular abnormalities that interact with genetic and environmental factors. Depression is twice as prevalent in women as in men, however, females remain underrepresented in preclinical research. In addition to the neurotransmission theory of depression, the inflammatory processes and the disrupted signaling pathways also play a crucial role in the pathophysiology of depression. The WKY rat strain has long been established as a model of depression. These rats demonstrate an exaggerated response to stress compared to other strains. WKY strain fail to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) and considered to be nonresponsive to antidepressant drugs. The hippocampus and the medial prefrontal cortex (mPFC) are thought to be an important regions for depression. Brain-derived neurotrophic factor (BDNF) play a vital role in the pathophysiology of depression. BDNF-stimulated signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)–/serine threonine kinase (Akt), also implicated in depression and treatment respons. In the present study, we have examined the effects of CMS on behavior and BDNF and PI3K/Akt signaling in the hippocampus and mPFC of female WKY rats.

Method: In the experiment, we used three months old Wistar (WI) and WKY female rats. Animals were divided in two groups: control and animals exposed to CMS for 6 weeks. On the last day of stress procedure, animals were tested in elevated plus maze to determine the levels of anxiety. Animals were then sacrificed and hippocampus and mPFC were isolated. Levels of BDNF and pAkt were determined by Western blot method. Data were analyzed using the two way ANOVA and Tuckey’s post-hoc test.

Results: WKY rats showed significantly decreased number of rearings (by 70%, p<0.01),decreased number of total arm entries (by 21%, p<0.05) and the time spent in the open arms (by 73%, p<0.001) of the elevated plus-maze compared to WI control group. WKY females had a significantly lower level of BDNF in the hippocampus (by 12%, p<0.05) and mPFC (by 16%, p<0.05) and pAkt (by 14%, p<0.01) only in mPFC as compared to the WI female rats. Exposure of WKY females to CMS enhanced an anxiety-like behavior and hypolomotion (decrease in number of rearings by 31%, p<0.05, number of total arm entries by 89%, p<0.001, and timevspent in the open arms by 92%, p<0.001), further down-expression of BDNF in both brain areas (in PFC: by 15%, p<0.001; in hippocampus: by 7%, p<0.05) and Akt phosphorylation in the mPFC (by 17%, p<0.05) as well as a decreased pAkt in the hippocampus (by 36%, p<0.001).

Conclusions: The difference in the balance of BDNF and PI3K/Akt signaling pathways may be relevant to the resistance of WKY rats to antidepressant drug treatment and may be useful for developing new targets for depression treatment, especially in females.",
journal = "Neuroscience Applied",
title = "Dysregulation of BDNF and PI3K/Akt signaling in the brain of female Wistar-Kyoto rats exposed to chronic mild stress",
volume = "2",
number = "Supplement 2",
pages = "102596",
doi = "10.1016/j.nsa.2023.102596"
}

Virijević, K., Spasojević, N., Stefanović, B., Ferizović, H., Janković, M.,& Dronjak, S.. (2023). Dysregulation of BDNF and PI3K/Akt signaling in the brain of female Wistar-Kyoto rats exposed to chronic mild stress. in Neuroscience Applied, 2(Supplement 2), 102596.
https://doi.org/10.1016/j.nsa.2023.102596

Virijević K, Spasojević N, Stefanović B, Ferizović H, Janković M, Dronjak S. Dysregulation of BDNF and PI3K/Akt signaling in the brain of female Wistar-Kyoto rats exposed to chronic mild stress. in Neuroscience Applied. 2023;2(Supplement 2):102596.
doi:10.1016/j.nsa.2023.102596 .

Virijević, Kristina, Spasojević, Nataša, Stefanović, Bojana, Ferizović, Harisa, Janković, Milica, Dronjak, Slađana, "Dysregulation of BDNF and PI3K/Akt signaling in the brain of female Wistar-Kyoto rats exposed to chronic mild stress" in Neuroscience Applied, 2, no. Supplement 2 (2023):102596,
https://doi.org/10.1016/j.nsa.2023.102596 . .