TY  - CONF
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Milošević, Katarina
AU  - Bjelobaba, Ivana
PY  - 2024
UR  - https://www.neurosteroids.unito.it/home-page
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6583
AB  - Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal
model of multiple sclerosis (MS) [1], which is a chronic neurodegenerative disease of the
central nervous system characterized with neuroinflammation and demyelination. MS
affects over 2 million people worldwide, mostly during the reproductive age, and it is far
more prevalent in women than in men [3]. Because fluctuations in sex hormone levels
during puberty, menarche, pregnancy, or menopause may impact the prevalence and
outcome of MS [2], we have undertaken efforts to elucidate the status of female
hypothalamic-pituitary-gonadal (HPG) axis during EAE.
EAE was induced by active immunization in 9-12-week-old female rats of Dark Agouti
strain. Disease symptoms, body weight changes and estrous cycle stages were monitored
daily. The animals were sacrificed at the onset of symptoms (Onset), at the peak of the
disease (Peak) and after the complete cessation of all symptoms (End). Non-immunized,
age-matched female rats were used as the Control group. All animals were sacrificed in the
diestrus stage of the estrous cycle. Luteinizing hormone (LH) and gonadal steroid levels
were measured, and the expression of relevant genes was assessed in hypothalamic, pituitary
and ovarian tissue.
In the hypothalamic tissue, a downregulation in Kiss1 expression was observed, while
Gnrh1 expression remained unaffected during the symptomatic phase of EAE. This was
accompanied by several-fold induction of the expression of astrocytes and
microglia/macrophages inflammatory markers – Gfap, Cd68, Ccl2, and Il1b. In the anterior
pituitary tissue, a downregulation in the expression of Gnrhr, Lhb and Cga was recorded,
along with significantly decreased LH levels in the circulation, at the peak of EAE.
Nevertheless, pituitary remained responsive to GnRH analogue challenge during the peak of
the disease. Pituitary Fshb was upregulated during onset and peak of EAE. An arrest in the
estrous cycle was registered, at the state of diestrus. Histological analysis of ovaries showed
maintenance of corpora lutea and increased number of atretic follicles at the peak of the
disease. In the ovarian tissue, steroidogenic machinery components – StAR, CYP11A1 and
3β-HSD, were upregulated at the gene and/or protein level. Accordingly, progesterone
levels were increased during the symptomatic phase of EAE, both in circulation and in
ovarian tissue. CYP17A1 gene and protein as well as testosterone and estradiol levels in the
ovary were significantly decreased. Interestingly, circulating testosterone levels were
slightly increased while circulating estradiol remained unchanged during EAE.
Overall, our results suggest that the changes in the function of the female reproductive axis
during EAE are due to a disruption of hypothalamic regulation, probably caused by
neuroinflammation. The arrest in the diestrus phase of the estrous cycle, together with
changes in ovarian steroidogenesis, contributes to a pseudopregnancy-like state in female
rats, which could represent an adaptation to the inflammatory process and implies a
temporary reduction in reproductive capacity to allow the system to fight the disease.
Furthermore, our results point to the importance of investigating the bidirectional
relationship between hormonal status and EAE/MS. This may also have an impact in the
clinical practice, as the approval of sex steroids as adjuvant therapy for MS could be
accelerated if they were prescribed only after careful monitoring of the individual patient’s
HPG axis status.
PB  - Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari
C3  - Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy
T1  - Hypothalamic-Pituitary-Ovarian Axis Is Affected in Dark Agouti Rats With Experimental Autoimmune Encephalomyelitis
SP  - 127
EP  - 128
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6583
ER  - 

@conference{
author = "Milošević, Ana and Janjić, Marija and Lavrnja, Irena and Savić, Danijela and Milošević, Katarina and Bjelobaba, Ivana",
year = "2024",
abstract = "Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal
model of multiple sclerosis (MS) [1], which is a chronic neurodegenerative disease of the
central nervous system characterized with neuroinflammation and demyelination. MS
affects over 2 million people worldwide, mostly during the reproductive age, and it is far
more prevalent in women than in men [3]. Because fluctuations in sex hormone levels
during puberty, menarche, pregnancy, or menopause may impact the prevalence and
outcome of MS [2], we have undertaken efforts to elucidate the status of female
hypothalamic-pituitary-gonadal (HPG) axis during EAE.
EAE was induced by active immunization in 9-12-week-old female rats of Dark Agouti
strain. Disease symptoms, body weight changes and estrous cycle stages were monitored
daily. The animals were sacrificed at the onset of symptoms (Onset), at the peak of the
disease (Peak) and after the complete cessation of all symptoms (End). Non-immunized,
age-matched female rats were used as the Control group. All animals were sacrificed in the
diestrus stage of the estrous cycle. Luteinizing hormone (LH) and gonadal steroid levels
were measured, and the expression of relevant genes was assessed in hypothalamic, pituitary
and ovarian tissue.
In the hypothalamic tissue, a downregulation in Kiss1 expression was observed, while
Gnrh1 expression remained unaffected during the symptomatic phase of EAE. This was
accompanied by several-fold induction of the expression of astrocytes and
microglia/macrophages inflammatory markers – Gfap, Cd68, Ccl2, and Il1b. In the anterior
pituitary tissue, a downregulation in the expression of Gnrhr, Lhb and Cga was recorded,
along with significantly decreased LH levels in the circulation, at the peak of EAE.
Nevertheless, pituitary remained responsive to GnRH analogue challenge during the peak of
the disease. Pituitary Fshb was upregulated during onset and peak of EAE. An arrest in the
estrous cycle was registered, at the state of diestrus. Histological analysis of ovaries showed
maintenance of corpora lutea and increased number of atretic follicles at the peak of the
disease. In the ovarian tissue, steroidogenic machinery components – StAR, CYP11A1 and
3β-HSD, were upregulated at the gene and/or protein level. Accordingly, progesterone
levels were increased during the symptomatic phase of EAE, both in circulation and in
ovarian tissue. CYP17A1 gene and protein as well as testosterone and estradiol levels in the
ovary were significantly decreased. Interestingly, circulating testosterone levels were
slightly increased while circulating estradiol remained unchanged during EAE.
Overall, our results suggest that the changes in the function of the female reproductive axis
during EAE are due to a disruption of hypothalamic regulation, probably caused by
neuroinflammation. The arrest in the diestrus phase of the estrous cycle, together with
changes in ovarian steroidogenesis, contributes to a pseudopregnancy-like state in female
rats, which could represent an adaptation to the inflammatory process and implies a
temporary reduction in reproductive capacity to allow the system to fight the disease.
Furthermore, our results point to the importance of investigating the bidirectional
relationship between hormonal status and EAE/MS. This may also have an impact in the
clinical practice, as the approval of sex steroids as adjuvant therapy for MS could be
accelerated if they were prescribed only after careful monitoring of the individual patient’s
HPG axis status.",
publisher = "Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari",
journal = "Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy",
title = "Hypothalamic-Pituitary-Ovarian Axis Is Affected in Dark Agouti Rats With Experimental Autoimmune Encephalomyelitis",
pages = "127-128",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6583"
}

Milošević, A., Janjić, M., Lavrnja, I., Savić, D., Milošević, K.,& Bjelobaba, I.. (2024). Hypothalamic-Pituitary-Ovarian Axis Is Affected in Dark Agouti Rats With Experimental Autoimmune Encephalomyelitis. in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy
Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari., 127-128.
https://hdl.handle.net/21.15107/rcub_ibiss_6583

Milošević A, Janjić M, Lavrnja I, Savić D, Milošević K, Bjelobaba I. Hypothalamic-Pituitary-Ovarian Axis Is Affected in Dark Agouti Rats With Experimental Autoimmune Encephalomyelitis. in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy. 2024;:127-128.
https://hdl.handle.net/21.15107/rcub_ibiss_6583 .

Milošević, Ana, Janjić, Marija, Lavrnja, Irena, Savić, Danijela, Milošević, Katarina, Bjelobaba, Ivana, "Hypothalamic-Pituitary-Ovarian Axis Is Affected in Dark Agouti Rats With Experimental Autoimmune Encephalomyelitis" in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy (2024):127-128,
https://hdl.handle.net/21.15107/rcub_ibiss_6583 .

TY  - CONF
AU  - Milošević, Ana
AU  - Savić, Danijela
AU  - Lavrnja, Irena
AU  - Milošević, Katarina
AU  - Bjelobaba, Ivana
AU  - Janjić, Marija
PY  - 2024
UR  - https://www.neurosteroids.unito.it/home-page
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6582
AB  - Multiple sclerosis (MS) is an autoimmune disease that usually occurs in both sexes during
the reproductive years. Various neuroendocrine changes have been described in this
inflammatory, demyelinating and debilitating disease, and many male MS patients have
lower blood testosterone levels. Our aim was to determine the extent of alterations in the
hypothalamic-pituitary-gonadal axis in the male rat model of MS, experimental autoimmune
encephalomyelitis (EAE). During the course of the disease, hypothalamic tissue showed a
transient upregulation of the inflammatory marker genes Gfap, Cd68, Ccl2 and Il1b,
accompanied by a downregulation of Gnrh1 expression and pituitary Gnrhr expression.
Serum levels of luteinizing hormone and testosterone were also reduced during the disease.
To better understand the causes of decreased testosterone production during EAE, we
examined the expression status of genes and proteins associated with steroidogenesis in the
testes. No changes in the number of interstitial cells were detected in the EAE animals, but
the expression of the gene insulin-like 3 was reduced at the peak of the disease, suggesting
that the functional capacity of Leydig cells was impaired. Consistent with this finding, the
expression of most steroidogenic enzyme genes and proteins was reduced during EAE,
including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation
were observed. Steroidogenesis recovered after the injection of hCG, a placental
gonadotropin or buserelin acetate, an analogue of gonadotropin-releasing hormone, at the
peak of EAE. Overall, our results are consistent with the hypothesis that impaired testicular
steroidogenesis originates upstream of the testes and that low serum LH levels are the main
cause of decreased testosterone levels during EAE.
PB  - Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari
C3  - Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy
T1  - The Hypothalamic-Pituitary-Gonadal Axis Is Suppressed During Experimental Autoimmune Encephalomyelitis in Male Rats
SP  - 124
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6582
ER  - 

@conference{
author = "Milošević, Ana and Savić, Danijela and Lavrnja, Irena and Milošević, Katarina and Bjelobaba, Ivana and Janjić, Marija",
year = "2024",
abstract = "Multiple sclerosis (MS) is an autoimmune disease that usually occurs in both sexes during
the reproductive years. Various neuroendocrine changes have been described in this
inflammatory, demyelinating and debilitating disease, and many male MS patients have
lower blood testosterone levels. Our aim was to determine the extent of alterations in the
hypothalamic-pituitary-gonadal axis in the male rat model of MS, experimental autoimmune
encephalomyelitis (EAE). During the course of the disease, hypothalamic tissue showed a
transient upregulation of the inflammatory marker genes Gfap, Cd68, Ccl2 and Il1b,
accompanied by a downregulation of Gnrh1 expression and pituitary Gnrhr expression.
Serum levels of luteinizing hormone and testosterone were also reduced during the disease.
To better understand the causes of decreased testosterone production during EAE, we
examined the expression status of genes and proteins associated with steroidogenesis in the
testes. No changes in the number of interstitial cells were detected in the EAE animals, but
the expression of the gene insulin-like 3 was reduced at the peak of the disease, suggesting
that the functional capacity of Leydig cells was impaired. Consistent with this finding, the
expression of most steroidogenic enzyme genes and proteins was reduced during EAE,
including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation
were observed. Steroidogenesis recovered after the injection of hCG, a placental
gonadotropin or buserelin acetate, an analogue of gonadotropin-releasing hormone, at the
peak of EAE. Overall, our results are consistent with the hypothesis that impaired testicular
steroidogenesis originates upstream of the testes and that low serum LH levels are the main
cause of decreased testosterone levels during EAE.",
publisher = "Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari",
journal = "Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy",
title = "The Hypothalamic-Pituitary-Gonadal Axis Is Suppressed During Experimental Autoimmune Encephalomyelitis in Male Rats",
pages = "124",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6582"
}

Milošević, A., Savić, D., Lavrnja, I., Milošević, K., Bjelobaba, I.,& Janjić, M.. (2024). The Hypothalamic-Pituitary-Gonadal Axis Is Suppressed During Experimental Autoimmune Encephalomyelitis in Male Rats. in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy
Milan: Dipartimento di Scienze Farmacologiche e Biomolecolari., 124.
https://hdl.handle.net/21.15107/rcub_ibiss_6582

Milošević A, Savić D, Lavrnja I, Milošević K, Bjelobaba I, Janjić M. The Hypothalamic-Pituitary-Gonadal Axis Is Suppressed During Experimental Autoimmune Encephalomyelitis in Male Rats. in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy. 2024;:124.
https://hdl.handle.net/21.15107/rcub_ibiss_6582 .

Milošević, Ana, Savić, Danijela, Lavrnja, Irena, Milošević, Katarina, Bjelobaba, Ivana, Janjić, Marija, "The Hypothalamic-Pituitary-Gonadal Axis Is Suppressed During Experimental Autoimmune Encephalomyelitis in Male Rats" in Abstract of individual lectures and free contributions: 12th International Meeting Steroids and Nervous System; 2024 Feb 24-27; Torino, Italy (2024):124,
https://hdl.handle.net/21.15107/rcub_ibiss_6582 .

TY  - CONF
AU  - Milošević, Katarina
AU  - Milošević, Ana
AU  - Živković, Anica
AU  - Stevanović, Ivana
AU  - Laketa, Danijela
AU  - Božić, Iva
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5875
AB  - Oxidative burst is a component of neuroinflammation whereby microglia-generated reactive oxygen species (ROS) either target pathogens or act as secondary messengers for microglial activation. In response to increased ROS during microglial activation, cytoprotective mechanisms are initiated primarily via Nrf2 activation and HO-1 expression. Agmatine is known to exert neuroprotective effect in vivo due to Nrf2 induction. While agmatine has been shown to activate the Nrf2/HO-1 signaling and protect macrophages from Lps-induced inflammation in vitro, its interaction with this pathway in activated microglia remains unexplored. Therefore, we sought to examine the potential of 100 μM agmatine as a pretreatment of Lps to activate Nrf2 in BV-2 microglia. In addition to cell viability, we analyzed the nuclear level of Nrf2 by Western blot and the expression of Hmox1 by PCR, as well as the protein level of HO-1. We also measured indicators of prooxidant and antioxidant activity: 4-HNE and total glutathione, respectively. Agmatine induces oxidative stress in non-stimulated microglia, as confirmed by the increase in the lipid peroxidation marker — 4-HNE, while cell viability stays preserved. Moreover, agmatine alone causes delayed Nrf2 nuclear overexpression and an increase in total glutathione content, eventually leading to an adaptive stress response. On the other hand, in Lps-stimulated microglia, agmatine prevents lipid peroxidation, readily upregulates the nuclear protein levels of Nrf2, which increases gene and protein expression of HO-1, and maintains delayed Nrf2 nuclear overexpression, resulting in increased total glutathione content associated with cytoprotection. Overall, we interpret agmatine-induced oxidative stress in non-activated microglia as triggering the adaptive response via Nrf2 and total glutathione, enabling them to cope with subsequent stressors, ie, Lps.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia
SP  - 106
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5875
ER  - 

@conference{
author = "Milošević, Katarina and Milošević, Ana and Živković, Anica and Stevanović, Ivana and Laketa, Danijela and Božić, Iva and Janjić, Marija and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2023",
abstract = "Oxidative burst is a component of neuroinflammation whereby microglia-generated reactive oxygen species (ROS) either target pathogens or act as secondary messengers for microglial activation. In response to increased ROS during microglial activation, cytoprotective mechanisms are initiated primarily via Nrf2 activation and HO-1 expression. Agmatine is known to exert neuroprotective effect in vivo due to Nrf2 induction. While agmatine has been shown to activate the Nrf2/HO-1 signaling and protect macrophages from Lps-induced inflammation in vitro, its interaction with this pathway in activated microglia remains unexplored. Therefore, we sought to examine the potential of 100 μM agmatine as a pretreatment of Lps to activate Nrf2 in BV-2 microglia. In addition to cell viability, we analyzed the nuclear level of Nrf2 by Western blot and the expression of Hmox1 by PCR, as well as the protein level of HO-1. We also measured indicators of prooxidant and antioxidant activity: 4-HNE and total glutathione, respectively. Agmatine induces oxidative stress in non-stimulated microglia, as confirmed by the increase in the lipid peroxidation marker — 4-HNE, while cell viability stays preserved. Moreover, agmatine alone causes delayed Nrf2 nuclear overexpression and an increase in total glutathione content, eventually leading to an adaptive stress response. On the other hand, in Lps-stimulated microglia, agmatine prevents lipid peroxidation, readily upregulates the nuclear protein levels of Nrf2, which increases gene and protein expression of HO-1, and maintains delayed Nrf2 nuclear overexpression, resulting in increased total glutathione content associated with cytoprotection. Overall, we interpret agmatine-induced oxidative stress in non-activated microglia as triggering the adaptive response via Nrf2 and total glutathione, enabling them to cope with subsequent stressors, ie, Lps.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia",
pages = "106",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5875"
}

Milošević, K., Milošević, A., Živković, A., Stevanović, I., Laketa, D., Božić, I., Janjić, M., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2023). Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 106.
https://hdl.handle.net/21.15107/rcub_ibiss_5875

Milošević K, Milošević A, Živković A, Stevanović I, Laketa D, Božić I, Janjić M, Bjelobaba I, Lavrnja I, Savić D. Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:106.
https://hdl.handle.net/21.15107/rcub_ibiss_5875 .

Milošević, Katarina, Milošević, Ana, Živković, Anica, Stevanović, Ivana, Laketa, Danijela, Božić, Iva, Janjić, Marija, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Agmatine upregulates Nrf2/HO-1 pathway in Lps-stimulated microglia" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):106,
https://hdl.handle.net/21.15107/rcub_ibiss_5875 .

TY  - CONF
AU  - Živković, Anica
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Milošević, Katarina
AU  - Božić, Iva
AU  - Trifunović, Svetlana
AU  - Savić, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5859
AB  - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous
system (CNS) that leads to severe neurological deficits. In past decades, numerous
studies have observed that anterior pituitary hormones play a pivotal role in regulation
of physiological immune response, as well as development and course of autoimmune
diseases.
Specifically, growth hormone (GH) and prolactin (PRL), peptide hormones
synthesized and secreted by the anterior pituitary, have been implicated in regulating
the immune system. Growth hormone secretion is positively regulated by the
hypothalamic growth hormone-releasing hormone (GHRH), while somatostatin (SST)
inhibits the release of GH.
Previous studies demonstrated that GHRH and GH are implicated in development of
experimental autoimmune encephalomyelitis (EAE), a representative animal model of
MS. Significantly higher PRL serum levels in MS patients were also reported.
We investigated spatiotemporal differences in GH and PRL levels in pituitaries from
EAE animals. Using immunolabeling and stereological methods we evaluated changes
in volume density of GH- and PRL-positive cells in pituitary gland of animals with
EAE compared to healthy controls. As we determined that there is no change in cell
volume density, we checked if there are any changes in gene expression of PRL, GH,
as well as GHRH and SST. Growth hormone and prolactin protein expression was
also measured in anterior pituitary. Our results show that, in addition to GH- and
PRL-positive cells volume density, there are no significant changes in gene and
protein expression in anterior pituitary during EAE.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats
SP  - 105
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5859
ER  - 

@conference{
author = "Živković, Anica and Milošević, Ana and Janjić, Marija and Milošević, Katarina and Božić, Iva and Trifunović, Svetlana and Savić, Danijela and Bjelobaba, Ivana and Lavrnja, Irena",
year = "2023",
abstract = "Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous
system (CNS) that leads to severe neurological deficits. In past decades, numerous
studies have observed that anterior pituitary hormones play a pivotal role in regulation
of physiological immune response, as well as development and course of autoimmune
diseases.
Specifically, growth hormone (GH) and prolactin (PRL), peptide hormones
synthesized and secreted by the anterior pituitary, have been implicated in regulating
the immune system. Growth hormone secretion is positively regulated by the
hypothalamic growth hormone-releasing hormone (GHRH), while somatostatin (SST)
inhibits the release of GH.
Previous studies demonstrated that GHRH and GH are implicated in development of
experimental autoimmune encephalomyelitis (EAE), a representative animal model of
MS. Significantly higher PRL serum levels in MS patients were also reported.
We investigated spatiotemporal differences in GH and PRL levels in pituitaries from
EAE animals. Using immunolabeling and stereological methods we evaluated changes
in volume density of GH- and PRL-positive cells in pituitary gland of animals with
EAE compared to healthy controls. As we determined that there is no change in cell
volume density, we checked if there are any changes in gene expression of PRL, GH,
as well as GHRH and SST. Growth hormone and prolactin protein expression was
also measured in anterior pituitary. Our results show that, in addition to GH- and
PRL-positive cells volume density, there are no significant changes in gene and
protein expression in anterior pituitary during EAE.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats",
pages = "105",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5859"
}

Živković, A., Milošević, A., Janjić, M., Milošević, K., Božić, I., Trifunović, S., Savić, D., Bjelobaba, I.,& Lavrnja, I.. (2023). Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 105.
https://hdl.handle.net/21.15107/rcub_ibiss_5859

Živković A, Milošević A, Janjić M, Milošević K, Božić I, Trifunović S, Savić D, Bjelobaba I, Lavrnja I. Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:105.
https://hdl.handle.net/21.15107/rcub_ibiss_5859 .

Živković, Anica, Milošević, Ana, Janjić, Marija, Milošević, Katarina, Božić, Iva, Trifunović, Svetlana, Savić, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, "Growth hormone and prolactin gene expression and protein levels are not affected during EAE in rats" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):105,
https://hdl.handle.net/21.15107/rcub_ibiss_5859 .

TY  - CONF
AU  - Milošević, Ana
AU  - Milošević, Katarina
AU  - Nikolić, Ljiljana
AU  - Bogdanović Pristov, Jelena
AU  - Božić, Iva
AU  - Živković, Anica
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5836
AB  - Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that controls
mammalian reproduction by acting on its receptor (GnRHR) expressed on pituitary
gonadotrope cells. While GnRHR signaling in gonadotropes is well described,
knowledge of GnRHR activation-related events at extrapituitary sites including
neurons is limited. It was proposed that GnRH analogs (GnRHa) induce distinct
changes in hippocampal gene expression, emotional processes, and cognitive
functions.
To explore neuronal GnRHR signaling we used the human neuroblastoma cell line
SH-SY5Y. Further, we explored the regional expression of Gnrhr in rat brain and
investigated the expression of several relevant genes in the hippocampus and preoptic
area of peripubertal male rats treated with GnRHa.
GNRHR is expressed in SH-SY5Y cell line, but its expression does not change after
adding GnRHa in the incubation media. Electrophysiological recordings confirmed
that GnRHa induced membrane depolarization but could not evoke action potentials.
In the rat brain, Gnrhr expression could be detected in the hippocampus, amygdala,
and hypothalamus, including the preoptic area. Prolonged treatment of peripubertal
rats with GnRHa had no effect on the expression of genes in the hippocampus
previously shown to be affected in the sheep model of delayed puberty.
These results imply that neuronal GnRHR is either differently coupled (not coupled
with Gq/11 protein), or that its membrane density is too low to induce transcriptional
events. More investigation is needed to elucidate the role(s) of GnRH-GnRHR
signaling in the brain.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - GnRHR signaling in neuronal cells: in vitro and in vivo data
SP  - 53
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5836
ER  - 

@conference{
author = "Milošević, Ana and Milošević, Katarina and Nikolić, Ljiljana and Bogdanović Pristov, Jelena and Božić, Iva and Živković, Anica and Lavrnja, Irena and Savić, Danijela and Janjić, Marija and Bjelobaba, Ivana",
year = "2023",
abstract = "Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide that controls
mammalian reproduction by acting on its receptor (GnRHR) expressed on pituitary
gonadotrope cells. While GnRHR signaling in gonadotropes is well described,
knowledge of GnRHR activation-related events at extrapituitary sites including
neurons is limited. It was proposed that GnRH analogs (GnRHa) induce distinct
changes in hippocampal gene expression, emotional processes, and cognitive
functions.
To explore neuronal GnRHR signaling we used the human neuroblastoma cell line
SH-SY5Y. Further, we explored the regional expression of Gnrhr in rat brain and
investigated the expression of several relevant genes in the hippocampus and preoptic
area of peripubertal male rats treated with GnRHa.
GNRHR is expressed in SH-SY5Y cell line, but its expression does not change after
adding GnRHa in the incubation media. Electrophysiological recordings confirmed
that GnRHa induced membrane depolarization but could not evoke action potentials.
In the rat brain, Gnrhr expression could be detected in the hippocampus, amygdala,
and hypothalamus, including the preoptic area. Prolonged treatment of peripubertal
rats with GnRHa had no effect on the expression of genes in the hippocampus
previously shown to be affected in the sheep model of delayed puberty.
These results imply that neuronal GnRHR is either differently coupled (not coupled
with Gq/11 protein), or that its membrane density is too low to induce transcriptional
events. More investigation is needed to elucidate the role(s) of GnRH-GnRHR
signaling in the brain.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "GnRHR signaling in neuronal cells: in vitro and in vivo data",
pages = "53",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5836"
}

Milošević, A., Milošević, K., Nikolić, L., Bogdanović Pristov, J., Božić, I., Živković, A., Lavrnja, I., Savić, D., Janjić, M.,& Bjelobaba, I.. (2023). GnRHR signaling in neuronal cells: in vitro and in vivo data. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 53.
https://hdl.handle.net/21.15107/rcub_ibiss_5836

Milošević A, Milošević K, Nikolić L, Bogdanović Pristov J, Božić I, Živković A, Lavrnja I, Savić D, Janjić M, Bjelobaba I. GnRHR signaling in neuronal cells: in vitro and in vivo data. in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:53.
https://hdl.handle.net/21.15107/rcub_ibiss_5836 .

Milošević, Ana, Milošević, Katarina, Nikolić, Ljiljana, Bogdanović Pristov, Jelena, Božić, Iva, Živković, Anica, Lavrnja, Irena, Savić, Danijela, Janjić, Marija, Bjelobaba, Ivana, "GnRHR signaling in neuronal cells: in vitro and in vivo data" in Book of abstracts: 8th Congress of Serbian Neuroscience Society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):53,
https://hdl.handle.net/21.15107/rcub_ibiss_5836 .

TY  - JOUR
AU  - Milošević, Ana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Milošević, Katarina
AU  - Skuljec, Jelena
AU  - Bjelobaba, Ivana
AU  - Janjić, Marija
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5757
AB  - Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and occurring far more prevalently in women than in men. In both MS and its animal models, sex hormones play important immunomodulatory roles. We have previously shown that experimental autoimmune encephalomyelitis (EAE) affects the hypothalamic-pituitary-gonadal axis in rats of both sexes and induces an arrest in the estrous cycle in females. To investigate the gonadal status in female rats with EAE, we explored ovarian morphometric parameters, circulating and intraovarian sex steroid levels, and the expression of steroidogenic machinery components in the ovarian tissue. A prolonged state of diestrus was recorded during the peak of EAE, with maintenance of the corpora lutea, elevated intraovarian progesterone levels, and increased gene and protein expression of StAR, similar to the state of pseudopregnancy. The decrease in CYP17A1 protein expression was followed by a decrease in ovarian testosterone and estradiol levels. On the contrary, serum testosterone levels were slightly increased. With unchanged serum estradiol levels, these results point at extra-gonadal sites of sex steroid biosynthesis and catabolism as important regulators of their circulating levels. Our study suggests alterations in the function of the female reproductive system during central autoimmunity and highlights the bidirectional relationships between hormonal status and EAE.
PB  - Basel: MDPI
T2  - Cells
T1  - Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis
IS  - 7
VL  - 12
DO  - 10.3390/cells12071045
SP  - 1054
ER  - 

@article{
author = "Milošević, Ana and Lavrnja, Irena and Savić, Danijela and Milošević, Katarina and Skuljec, Jelena and Bjelobaba, Ivana and Janjić, Marija",
year = "2023",
abstract = "Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and occurring far more prevalently in women than in men. In both MS and its animal models, sex hormones play important immunomodulatory roles. We have previously shown that experimental autoimmune encephalomyelitis (EAE) affects the hypothalamic-pituitary-gonadal axis in rats of both sexes and induces an arrest in the estrous cycle in females. To investigate the gonadal status in female rats with EAE, we explored ovarian morphometric parameters, circulating and intraovarian sex steroid levels, and the expression of steroidogenic machinery components in the ovarian tissue. A prolonged state of diestrus was recorded during the peak of EAE, with maintenance of the corpora lutea, elevated intraovarian progesterone levels, and increased gene and protein expression of StAR, similar to the state of pseudopregnancy. The decrease in CYP17A1 protein expression was followed by a decrease in ovarian testosterone and estradiol levels. On the contrary, serum testosterone levels were slightly increased. With unchanged serum estradiol levels, these results point at extra-gonadal sites of sex steroid biosynthesis and catabolism as important regulators of their circulating levels. Our study suggests alterations in the function of the female reproductive system during central autoimmunity and highlights the bidirectional relationships between hormonal status and EAE.",
publisher = "Basel: MDPI",
journal = "Cells",
title = "Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis",
number = "7",
volume = "12",
doi = "10.3390/cells12071045",
pages = "1054"
}

Milošević, A., Lavrnja, I., Savić, D., Milošević, K., Skuljec, J., Bjelobaba, I.,& Janjić, M.. (2023). Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis. in Cells
Basel: MDPI., 12(7), 1054.
https://doi.org/10.3390/cells12071045

Milošević A, Lavrnja I, Savić D, Milošević K, Skuljec J, Bjelobaba I, Janjić M. Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis. in Cells. 2023;12(7):1054.
doi:10.3390/cells12071045 .

Milošević, Ana, Lavrnja, Irena, Savić, Danijela, Milošević, Katarina, Skuljec, Jelena, Bjelobaba, Ivana, Janjić, Marija, "Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis" in Cells, 12, no. 7 (2023):1054,
https://doi.org/10.3390/cells12071045 . .

TY  - JOUR
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2022
UR  - https://www.mdpi.com/1422-0067/23/7/3561
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC8998340
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4948
AB  - Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.
PB  - Basel: MDPI
T2  - International Journal of Molecular Sciences
T1  - Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.
IS  - 7
VL  - 23
DO  - 10.3390/ijms23073561
SP  - 3561
ER  - 

@article{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2022",
abstract = "Neuroinflammation and microglial activation, common components of most neurodegenerative diseases, can be imitated in vitro by challenging microglia cells with Lps. We here aimed to evaluate the effects of agmatine pretreatment on Lps-induced oxidative stress in a mouse microglial BV-2 cell line. Our findings show that agmatine suppresses nitrosative and oxidative burst in Lps-stimulated microglia by reducing iNOS and XO activity and decreasing O2- levels, arresting lipid peroxidation, increasing total glutathione content, and preserving GR and CAT activity. In accordance with these results, agmatine suppresses inflammatory NF-kB, and stimulates antioxidant Nrf2 pathway, resulting in decreased TNF, IL-1 beta, and IL-6 release, and reduced iNOS and COX-2 levels. Together with increased ARG1, CD206 and HO-1 levels, our results imply that, in inflammatory conditions, agmatine pushes microglia towards an anti-inflammatory phenotype. Interestingly, we also discovered that agmatine alone increases lipid peroxidation end product levels, induces Nrf2 activation, increases total glutathione content, and GPx activity. Thus, we hypothesize that some of the effects of agmatine, observed in activated microglia, may be mediated by induced oxidative stress and adaptive response, prior to Lps stimulation.",
publisher = "Basel: MDPI",
journal = "International Journal of Molecular Sciences",
title = "Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.",
number = "7",
volume = "23",
doi = "10.3390/ijms23073561",
pages = "3561"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Janjić, M., Laketa, D., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2022). Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.. in International Journal of Molecular Sciences
Basel: MDPI., 23(7), 3561.
https://doi.org/10.3390/ijms23073561

Milošević K, Stevanović I, Božić I, Milošević A, Janjić M, Laketa D, Bjelobaba I, Lavrnja I, Savić D. Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response.. in International Journal of Molecular Sciences. 2022;23(7):3561.
doi:10.3390/ijms23073561 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response." in International Journal of Molecular Sciences, 23, no. 7 (2022):3561,
https://doi.org/10.3390/ijms23073561 . .

TY  - CONF
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Bjelobaba, Ivana
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5749
AB  - Prekomerna neuroinflamacija i mikroglijska aktivacija su uključene u patologiju mnogih neurodegenerativnih bolesti i mogu se simulirati u in vitro sistemu mikroglijskih ćelija primenom bakterijskog lipolisaharida (engl. Lipopolisaharide, LPS). Naša studija imala je za cilj da proceni efekte  pretretmana agmatinom na LPS-om izazvani oksidativni stres u BV-2 mišjoj mikroglijskoj ćelijskoj liniji. Pokazano je da u LPS-om stimulisanoj mikrogliji agmatin smanjuje enzimsku aktivnost iNOS i ksantin oksidaze (engl. Xanthine oxidase, XO), kao i nivo O2−, zaustavlja lipidnu peroksidaciju, povećava količinu ukupnog glutationa i omogućava da se delimično očuva aktivnost glutation reduktaze i katalaze, čime redukuje azotni i oksidativni stres. Agmatin utiče i na dva glavna signalna puta (NF-kB i Nrf2) uključena u inflamaciju, odnosno, antioksidativnu zaštitu, smanjujući tako nivo iNOS i COX-2, kao i oslobađanje TNF, IL-1β i IL-6. Istovremeno povećava se nivo ARG1, CD206 i HO-1, iz čega proizilazi da u uslovima inflamacije agmatin moduliše aktivaciju mikroglije u pravcu antiinflamacijskog fenotipa. Pokazali smo i da sam agmatin kod BV-2 ćelija dovodi do porasta nivoa krajnjih produkata lipidne peroksidacije, ali i ukupnog glutationa, aktivnosti glutation peroksidaze i aktivacije Nrf2 puta. Ovi rezultati podržavaju hipotezu da su agmatinom izazvani oksidativni stres i adaptivni odgovor, koji prethode stimulaciji LPS-om, odgovorni za efekte agmatina u aktiviranoj mikrogliji.
AB  - Прекомерена неуроинфламација и микроглијска активација су укључене у
патологију многих неуродегенеративних болести и могу се симулирати у in vitro
систему микроглијских ћелија применом бактеријског липолисахарида (енгл.
Lipopolisaharide, LPS). Наша студија имала је за циљ да процени ефекте
претретмана агматином на LPS-ом изазвани оксидативни стрес у BV-2 мишјој
микроглијској ћелијској линији. Показано је да у LPS-ом стимулисаној микроглији
агматин смањује ензимску активност iNOS и ксантин оксидазе (енгл. Xanthine
oxidase, XO), као и ниво O2−, зауставља липидну пероксидацију, повећава количину
укупног глутатиона и омогућава да се делимично очува активност глутатион
редуктазе и каталазе, чиме редукује азотни и оксидативни стрес. Агматин утиче и
на два главна сигнална пута (NF-kB и Nrf2) укључена у инфламацију, односно,
антиоксидативну заштиту, смањујући тако ниво iNOS и COX-2, као и ослобађање
TNF, IL-1β и IL-6. Истовремено повећава се ниво ARG1, CD206 и HO-1, из чега
произилази да у условима инфламације агматин модулише активацију микроглије
у правцу антиинфламацијског фенотипа. Показали смо и да сам агматин код BV-2
ћелија доводи до пораста нивоа крајњих продуката липидне пероксидације, али и
укупног глутатиона, активности глутатион пероксидазе и активације Nrf2 пута.
Ови резултати подржавају хипотезу да су агматином изазвани оксидативни стрес и
адаптивни одговор, који претходе стимулацији LPS-ом, одговорни за ефекте
агматина у активираној микроглији.
PB  - Belgrade: Serbian Biological Society
C3  - Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
T1  - Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom
T1  - Утицај агматина на оксидативни и инфламацијски одговор микроглијских ћелија активираних бактеријским липополисахаридом
SP  - 290
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5749
ER  - 

@conference{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Bjelobaba, Ivana and Lavrnja, Irena and Savić, Danijela",
year = "2022",
abstract = "Prekomerna neuroinflamacija i mikroglijska aktivacija su uključene u patologiju mnogih neurodegenerativnih bolesti i mogu se simulirati u in vitro sistemu mikroglijskih ćelija primenom bakterijskog lipolisaharida (engl. Lipopolisaharide, LPS). Naša studija imala je za cilj da proceni efekte  pretretmana agmatinom na LPS-om izazvani oksidativni stres u BV-2 mišjoj mikroglijskoj ćelijskoj liniji. Pokazano je da u LPS-om stimulisanoj mikrogliji agmatin smanjuje enzimsku aktivnost iNOS i ksantin oksidaze (engl. Xanthine oxidase, XO), kao i nivo O2−, zaustavlja lipidnu peroksidaciju, povećava količinu ukupnog glutationa i omogućava da se delimično očuva aktivnost glutation reduktaze i katalaze, čime redukuje azotni i oksidativni stres. Agmatin utiče i na dva glavna signalna puta (NF-kB i Nrf2) uključena u inflamaciju, odnosno, antioksidativnu zaštitu, smanjujući tako nivo iNOS i COX-2, kao i oslobađanje TNF, IL-1β i IL-6. Istovremeno povećava se nivo ARG1, CD206 i HO-1, iz čega proizilazi da u uslovima inflamacije agmatin moduliše aktivaciju mikroglije u pravcu antiinflamacijskog fenotipa. Pokazali smo i da sam agmatin kod BV-2 ćelija dovodi do porasta nivoa krajnjih produkata lipidne peroksidacije, ali i ukupnog glutationa, aktivnosti glutation peroksidaze i aktivacije Nrf2 puta. Ovi rezultati podržavaju hipotezu da su agmatinom izazvani oksidativni stres i adaptivni odgovor, koji prethode stimulaciji LPS-om, odgovorni za efekte agmatina u aktiviranoj mikrogliji., Прекомерена неуроинфламација и микроглијска активација су укључене у
патологију многих неуродегенеративних болести и могу се симулирати у in vitro
систему микроглијских ћелија применом бактеријског липолисахарида (енгл.
Lipopolisaharide, LPS). Наша студија имала је за циљ да процени ефекте
претретмана агматином на LPS-ом изазвани оксидативни стрес у BV-2 мишјој
микроглијској ћелијској линији. Показано је да у LPS-ом стимулисаној микроглији
агматин смањује ензимску активност iNOS и ксантин оксидазе (енгл. Xanthine
oxidase, XO), као и ниво O2−, зауставља липидну пероксидацију, повећава количину
укупног глутатиона и омогућава да се делимично очува активност глутатион
редуктазе и каталазе, чиме редукује азотни и оксидативни стрес. Агматин утиче и
на два главна сигнална пута (NF-kB и Nrf2) укључена у инфламацију, односно,
антиоксидативну заштиту, смањујући тако ниво iNOS и COX-2, као и ослобађање
TNF, IL-1β и IL-6. Истовремено повећава се ниво ARG1, CD206 и HO-1, из чега
произилази да у условима инфламације агматин модулише активацију микроглије
у правцу антиинфламацијског фенотипа. Показали смо и да сам агматин код BV-2
ћелија доводи до пораста нивоа крајњих продуката липидне пероксидације, али и
укупног глутатиона, активности глутатион пероксидазе и активације Nrf2 пута.
Ови резултати подржавају хипотезу да су агматином изазвани оксидативни стрес и
адаптивни одговор, који претходе стимулацији LPS-ом, одговорни за ефекте
агматина у активираној микроглији.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia",
title = "Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom, Утицај агматина на оксидативни и инфламацијски одговор микроглијских ћелија активираних бактеријским липополисахаридом",
pages = "290",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5749"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Janjić, M., Laketa, D., Bjelobaba, I., Lavrnja, I.,& Savić, D.. (2022). Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society., 290.
https://hdl.handle.net/21.15107/rcub_ibiss_5749

Milošević K, Stevanović I, Božić I, Milošević A, Janjić M, Laketa D, Bjelobaba I, Lavrnja I, Savić D. Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;:290.
https://hdl.handle.net/21.15107/rcub_ibiss_5749 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Bjelobaba, Ivana, Lavrnja, Irena, Savić, Danijela, "Uticaj agmatina na oksidativni i inflamacijski odgovor mikroglijskih ćelija aktiviranih bakterijskim lipopolisaharidom" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia (2022):290,
https://hdl.handle.net/21.15107/rcub_ibiss_5749 .

TY  - CONF
AU  - Milošević, Katarina
AU  - Stevanović, Ivana
AU  - Božić, Iva
AU  - Milošević, Ana
AU  - Jakovljević, Marija
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Laketa, Danijela
AU  - Lavrnja, Irena
AU  - Savić, Danijela
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6003
AB  - Mitochondria play a key role in energy metabolism and regulate some of the principal cellular processes such as the production of ATP and reactive oxygen species, as well as a regulation of apoptotic cell death. Mitochondrial dysfunction and oxidative stress are common threads in most neurodegenerative disorders, which are also accompanied by chronic microglial activation. Agmatine, neuromodulatory polyamine, was shown to exhibit neuroprotective effects in oxidative stress conditions. Therefore, the goal of this study was to determine the ability of agmatine to preserve mitochondrial function and prevent apoptosis during neuroinflammation.
The effects of 100 µM agmatine on cellular energy status and cell death were examined in LPS-stimulated BV2 microglial cell line. To detect changes in mitochondrial membrane potential, TMRE fluorescent assay was performed, while the changes in intracellular ATP concentration were determined by bioluminescent assay, 6h, and 24h after LPS stimulation. The expression of apoptosis regulators Bax and Bcl2 was assessed by Western blot analysis and the Bax/Bcl2 ratio was determined.
Agmatine increases mitochondrial membrane potential, indicating its protective role during mitochondrial insult caused by LPS stimulation. LPS and agmatine administrated separately, increase intracellular ATP levels, however, agmatine treatment followed by LPS stimulation enhances ATP production even further, at both time points. Moreover, agmatine shows an antiapoptotic effect by reduction of Bax/Bcl2 ratio in comparison to LPS stimulation.
We conclude that the results of this study indicate the capacity of agmatine to protect mitochondrial function and suppress apoptosis, which may be beneficial in neurodegenerative disorders and
neuroinflammation.
PB  - Federation of European Neuroscience Societies
C3  - Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
T1  - Agmatine protects mitochondria in LPS-stimulated microglia
SP  - 285
EP  - 286
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6003
ER  - 

@conference{
author = "Milošević, Katarina and Stevanović, Ivana and Božić, Iva and Milošević, Ana and Jakovljević, Marija and Janjić, Marija and Bjelobaba, Ivana and Laketa, Danijela and Lavrnja, Irena and Savić, Danijela",
year = "2021",
abstract = "Mitochondria play a key role in energy metabolism and regulate some of the principal cellular processes such as the production of ATP and reactive oxygen species, as well as a regulation of apoptotic cell death. Mitochondrial dysfunction and oxidative stress are common threads in most neurodegenerative disorders, which are also accompanied by chronic microglial activation. Agmatine, neuromodulatory polyamine, was shown to exhibit neuroprotective effects in oxidative stress conditions. Therefore, the goal of this study was to determine the ability of agmatine to preserve mitochondrial function and prevent apoptosis during neuroinflammation.
The effects of 100 µM agmatine on cellular energy status and cell death were examined in LPS-stimulated BV2 microglial cell line. To detect changes in mitochondrial membrane potential, TMRE fluorescent assay was performed, while the changes in intracellular ATP concentration were determined by bioluminescent assay, 6h, and 24h after LPS stimulation. The expression of apoptosis regulators Bax and Bcl2 was assessed by Western blot analysis and the Bax/Bcl2 ratio was determined.
Agmatine increases mitochondrial membrane potential, indicating its protective role during mitochondrial insult caused by LPS stimulation. LPS and agmatine administrated separately, increase intracellular ATP levels, however, agmatine treatment followed by LPS stimulation enhances ATP production even further, at both time points. Moreover, agmatine shows an antiapoptotic effect by reduction of Bax/Bcl2 ratio in comparison to LPS stimulation.
We conclude that the results of this study indicate the capacity of agmatine to protect mitochondrial function and suppress apoptosis, which may be beneficial in neurodegenerative disorders and
neuroinflammation.",
publisher = "Federation of European Neuroscience Societies",
journal = "Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland",
title = "Agmatine protects mitochondria in LPS-stimulated microglia",
pages = "285-286",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6003"
}

Milošević, K., Stevanović, I., Božić, I., Milošević, A., Jakovljević, M., Janjić, M., Bjelobaba, I., Laketa, D., Lavrnja, I.,& Savić, D.. (2021). Agmatine protects mitochondria in LPS-stimulated microglia. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland
Federation of European Neuroscience Societies., 285-286.
https://hdl.handle.net/21.15107/rcub_ibiss_6003

Milošević K, Stevanović I, Božić I, Milošević A, Jakovljević M, Janjić M, Bjelobaba I, Laketa D, Lavrnja I, Savić D. Agmatine protects mitochondria in LPS-stimulated microglia. in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland. 2021;:285-286.
https://hdl.handle.net/21.15107/rcub_ibiss_6003 .

Milošević, Katarina, Stevanović, Ivana, Božić, Iva, Milošević, Ana, Jakovljević, Marija, Janjić, Marija, Bjelobaba, Ivana, Laketa, Danijela, Lavrnja, Irena, Savić, Danijela, "Agmatine protects mitochondria in LPS-stimulated microglia" in Book of Abstracts: Virtual FENS Regional Meeting 2021; 2021 Aug 25-27; Krakow, Poland (2021):285-286,
https://hdl.handle.net/21.15107/rcub_ibiss_6003 .

TY  - JOUR
AU  - Trifunović, Svetlana
AU  - Stevanović, Ivana
AU  - Milošević, Ana
AU  - Ristić, Nataša
AU  - Janjić, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Jakovljević, Marija
AU  - Milošević, Katarina
AU  - Laketa, Danijela
AU  - Lavrnja, Irena
PY  - 2021
UR  - https://www.frontiersin.org/articles/10.3389/fnins.2021.649485/full
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4436
AB  - Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic-pituitary-adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.
PB  - Lausanne: Frontiers Media SA
T2  - Frontiers in Neuroscience
T1  - The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.
VL  - 15
DO  - 10.3389/fnins.2021.649485
SP  - 649485
ER  - 

@article{
author = "Trifunović, Svetlana and Stevanović, Ivana and Milošević, Ana and Ristić, Nataša and Janjić, Marija and Bjelobaba, Ivana and Savić, Danijela and Božić, Iva and Jakovljević, Marija and Milošević, Katarina and Laketa, Danijela and Lavrnja, Irena",
year = "2021",
abstract = "Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic-pituitary-adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.",
publisher = "Lausanne: Frontiers Media SA",
journal = "Frontiers in Neuroscience",
title = "The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.",
volume = "15",
doi = "10.3389/fnins.2021.649485",
pages = "649485"
}

Trifunović, S., Stevanović, I., Milošević, A., Ristić, N., Janjić, M., Bjelobaba, I., Savić, D., Božić, I., Jakovljević, M., Milošević, K., Laketa, D.,& Lavrnja, I.. (2021). The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.. in Frontiers in Neuroscience
Lausanne: Frontiers Media SA., 15, 649485.
https://doi.org/10.3389/fnins.2021.649485

Trifunović S, Stevanović I, Milošević A, Ristić N, Janjić M, Bjelobaba I, Savić D, Božić I, Jakovljević M, Milošević K, Laketa D, Lavrnja I. The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators.. in Frontiers in Neuroscience. 2021;15:649485.
doi:10.3389/fnins.2021.649485 .

Trifunović, Svetlana, Stevanović, Ivana, Milošević, Ana, Ristić, Nataša, Janjić, Marija, Bjelobaba, Ivana, Savić, Danijela, Božić, Iva, Jakovljević, Marija, Milošević, Katarina, Laketa, Danijela, Lavrnja, Irena, "The Function of the Hypothalamic-Pituitary-Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators." in Frontiers in Neuroscience, 15 (2021):649485,
https://doi.org/10.3389/fnins.2021.649485 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Bjelobaba, Ivana
AU  - Božić, Iva
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Stojilković, Stanko S.
AU  - Janjić, Marija
PY  - 2021
UR  - https://doi.org/10.1038/s41598-021-88305-5
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4248
AB  - Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood testosterone levels, which was also observed in male rats during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To better understand the causes of decreased testosterone production during EAE, we investigated the expression status of genes and proteins associated with steroidogenesis in the testes. No changes in the number of interstitial cells were observed in EAE animals, but the expression of the insulin-like 3 gene was reduced at the peak of the disease, implying that the Leydig cell functional capacity was affected. Consistent with this finding, the expression of most steroidogenic enzyme genes and proteins was reduced during EAE, including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation were observed. Recovery of steroidogenesis was observed after injection of hCG, the placental gonadotropin, or buserelin acetate, a gonadotropin-releasing hormone analogue, at the peak of EAE. Together, our results are consistent with the hypothesis that impaired testicular steroidogenesis originates upstream of the testes and that low serum LH is the main cause of decreased testosterone levels during EAE.
PB  - Springer Science and Business Media LLC
T2  - Scientific Reports
T1  - Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats
IS  - 1
VL  - 11
DO  - 10.1038/s41598-021-88305-5
SP  - 8996
ER  - 

@article{
author = "Milošević, Ana and Bjelobaba, Ivana and Božić, Iva and Lavrnja, Irena and Savić, Danijela and Milošević, Katarina and Jakovljević, Marija and Stojilković, Stanko S. and Janjić, Marija",
year = "2021",
abstract = "Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood testosterone levels, which was also observed in male rats during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To better understand the causes of decreased testosterone production during EAE, we investigated the expression status of genes and proteins associated with steroidogenesis in the testes. No changes in the number of interstitial cells were observed in EAE animals, but the expression of the insulin-like 3 gene was reduced at the peak of the disease, implying that the Leydig cell functional capacity was affected. Consistent with this finding, the expression of most steroidogenic enzyme genes and proteins was reduced during EAE, including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation were observed. Recovery of steroidogenesis was observed after injection of hCG, the placental gonadotropin, or buserelin acetate, a gonadotropin-releasing hormone analogue, at the peak of EAE. Together, our results are consistent with the hypothesis that impaired testicular steroidogenesis originates upstream of the testes and that low serum LH is the main cause of decreased testosterone levels during EAE.",
publisher = "Springer Science and Business Media LLC",
journal = "Scientific Reports",
title = "Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats",
number = "1",
volume = "11",
doi = "10.1038/s41598-021-88305-5",
pages = "8996"
}

Milošević, A., Bjelobaba, I., Božić, I., Lavrnja, I., Savić, D., Milošević, K., Jakovljević, M., Stojilković, S. S.,& Janjić, M.. (2021). Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats. in Scientific Reports
Springer Science and Business Media LLC., 11(1), 8996.
https://doi.org/10.1038/s41598-021-88305-5

Milošević A, Bjelobaba I, Božić I, Lavrnja I, Savić D, Milošević K, Jakovljević M, Stojilković SS, Janjić M. Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats. in Scientific Reports. 2021;11(1):8996.
doi:10.1038/s41598-021-88305-5 .

Milošević, Ana, Bjelobaba, Ivana, Božić, Iva, Lavrnja, Irena, Savić, Danijela, Milošević, Katarina, Jakovljević, Marija, Stojilković, Stanko S., Janjić, Marija, "Testicular steroidogenesis is suppressed during experimental autoimmune encephalomyelitis in rats" in Scientific Reports, 11, no. 1 (2021):8996,
https://doi.org/10.1038/s41598-021-88305-5 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Peković, Sanja
AU  - Stojilkovic, Stanko S.
AU  - Bjelobaba, Ivana
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32592862
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6149
AB  - Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.
PB  - Elsevier BV
PB  - Elsevier
T2  - Brain, Behavior, and Immunity
T1  - The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.
VL  - 89
DO  - 10.1016/j.bbi.2020.06.025
SP  - 233
EP  - 244
ER  - 

@article{
author = "Milošević, Ana and Janjić, Marija and Lavrnja, Irena and Savić, Danijela and Božić, Iva and Milošević, Katarina and Jakovljević, Marija and Peković, Sanja and Stojilkovic, Stanko S. and Bjelobaba, Ivana",
year = "2020",
abstract = "Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.",
publisher = "Elsevier BV, Elsevier",
journal = "Brain, Behavior, and Immunity",
title = "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.",
volume = "89",
doi = "10.1016/j.bbi.2020.06.025",
pages = "233-244"
}

Milošević, A., Janjić, M., Lavrnja, I., Savić, D., Božić, I., Milošević, K., Jakovljević, M., Peković, S., Stojilkovic, S. S.,& Bjelobaba, I.. (2020). The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity
Elsevier BV., 89, 233-244.
https://doi.org/10.1016/j.bbi.2020.06.025

Milošević A, Janjić M, Lavrnja I, Savić D, Božić I, Milošević K, Jakovljević M, Peković S, Stojilkovic SS, Bjelobaba I. The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity. 2020;89:233-244.
doi:10.1016/j.bbi.2020.06.025 .

Milošević, Ana, Janjić, Marija, Lavrnja, Irena, Savić, Danijela, Božić, Iva, Milošević, Katarina, Jakovljević, Marija, Peković, Sanja, Stojilkovic, Stanko S., Bjelobaba, Ivana, "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis." in Brain, Behavior, and Immunity, 89 (2020):233-244,
https://doi.org/10.1016/j.bbi.2020.06.025 . .

TY  - JOUR
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Lavrnja, Irena
AU  - Savić, Danijela
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Jakovljević, Marija
AU  - Peković, Sanja
AU  - Stojilkovic, Stanko S.
AU  - Bjelobaba, Ivana
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32592862
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3762
AB  - Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.
PB  - Elsevier BV
T2  - Brain, Behavior, and Immunity
T1  - The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.
VL  - 89
DO  - 10.1016/j.bbi.2020.06.025
SP  - DOI:10.1016/j.bbi.2020.06.025
EP  - 244
ER  - 

@article{
author = "Milošević, Ana and Janjić, Marija and Lavrnja, Irena and Savić, Danijela and Božić, Iva and Milošević, Katarina and Jakovljević, Marija and Peković, Sanja and Stojilkovic, Stanko S. and Bjelobaba, Ivana",
year = "2020",
abstract = "Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis. During the disease course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum luteinizing hormone and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sex-specific changes downstream the axis.",
publisher = "Elsevier BV",
journal = "Brain, Behavior, and Immunity",
title = "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.",
volume = "89",
doi = "10.1016/j.bbi.2020.06.025",
pages = "DOI:10.1016/j.bbi.2020.06.025-244"
}

Milošević, A., Janjić, M., Lavrnja, I., Savić, D., Božić, I., Milošević, K., Jakovljević, M., Peković, S., Stojilkovic, S. S.,& Bjelobaba, I.. (2020). The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity
Elsevier BV., 89, DOI:10.1016/j.bbi.2020.06.025-244.
https://doi.org/10.1016/j.bbi.2020.06.025

Milošević A, Janjić M, Lavrnja I, Savić D, Božić I, Milošević K, Jakovljević M, Peković S, Stojilkovic SS, Bjelobaba I. The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis.. in Brain, Behavior, and Immunity. 2020;89:DOI:10.1016/j.bbi.2020.06.025-244.
doi:10.1016/j.bbi.2020.06.025 .

Milošević, Ana, Janjić, Marija, Lavrnja, Irena, Savić, Danijela, Božić, Iva, Milošević, Katarina, Jakovljević, Marija, Peković, Sanja, Stojilkovic, Stanko S., Bjelobaba, Ivana, "The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis." in Brain, Behavior, and Immunity, 89 (2020):DOI:10.1016/j.bbi.2020.06.025-244,
https://doi.org/10.1016/j.bbi.2020.06.025 . .

TY  - CONF
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Janjić, Marija
AU  - Savić, Danijela
AU  - Laketa, Danijela
AU  - Jakovljević, Marija
AU  - Milošević, Ana
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6006
AB  - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, neurodegeneration and gliosis. It is considered as a perplexing multifactorial disease in which the neuroendocrine system plays an important role. Growth hormone (GH) is synthesized and secreted by the somatotroph cells of the anterior pituitary. GH secretion is positively regulated by the hypothalamic factor GHRH and exerts its effects through interaction with the GH receptor (GHR), a member of the class I cytokine receptor family. It was demonstrated that neurons and astrocytes also produce GH and that GHR is widely expressed in the CNS. Nonetheless, it is not known whether expression pattern of GHR changes in the CNS during MS. We investigated GHR expression in the spinal cord during the course of experimental autoimmune encephalomyelitis (EAE), animal model of MS that is broadly used. Our results show that GHR is diminished on mRNA and protein level during EAE. Double immunofluorescence studies demonstrated that GHR is expressed in different cell types in the spinal cord in physiological conditions, including astrocytes and microglia. This expression pattern does not change extensively after the onset of EAE. However, at the peak of disease GHR is absent from astrocytes in the white and grey matter, but still present in microglia, although to a lesser degree. At the end of disease, when the animals have recovered, GHR expression is similar to control conditions. Our results point to complex involvement of GHR in the pathology of EAE.
PB  - Belgrade : Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis
EP  - 212
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6006
ER  - 

@conference{
author = "Božić, Iva and Milošević, Katarina and Janjić, Marija and Savić, Danijela and Laketa, Danijela and Jakovljević, Marija and Milošević, Ana and Peković, Sanja and Lavrnja, Irena",
year = "2019",
abstract = "Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination, neurodegeneration and gliosis. It is considered as a perplexing multifactorial disease in which the neuroendocrine system plays an important role. Growth hormone (GH) is synthesized and secreted by the somatotroph cells of the anterior pituitary. GH secretion is positively regulated by the hypothalamic factor GHRH and exerts its effects through interaction with the GH receptor (GHR), a member of the class I cytokine receptor family. It was demonstrated that neurons and astrocytes also produce GH and that GHR is widely expressed in the CNS. Nonetheless, it is not known whether expression pattern of GHR changes in the CNS during MS. We investigated GHR expression in the spinal cord during the course of experimental autoimmune encephalomyelitis (EAE), animal model of MS that is broadly used. Our results show that GHR is diminished on mRNA and protein level during EAE. Double immunofluorescence studies demonstrated that GHR is expressed in different cell types in the spinal cord in physiological conditions, including astrocytes and microglia. This expression pattern does not change extensively after the onset of EAE. However, at the peak of disease GHR is absent from astrocytes in the white and grey matter, but still present in microglia, although to a lesser degree. At the end of disease, when the animals have recovered, GHR expression is similar to control conditions. Our results point to complex involvement of GHR in the pathology of EAE.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis",
pages = "212",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6006"
}

Božić, I., Milošević, K., Janjić, M., Savić, D., Laketa, D., Jakovljević, M., Milošević, A., Peković, S.,& Lavrnja, I.. (2019). Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade : Serbian Neuroscience Society..
https://hdl.handle.net/21.15107/rcub_ibiss_6006

Božić I, Milošević K, Janjić M, Savić D, Laketa D, Jakovljević M, Milošević A, Peković S, Lavrnja I. Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:null-212.
https://hdl.handle.net/21.15107/rcub_ibiss_6006 .

Božić, Iva, Milošević, Katarina, Janjić, Marija, Savić, Danijela, Laketa, Danijela, Jakovljević, Marija, Milošević, Ana, Peković, Sanja, Lavrnja, Irena, "Expression of growth hormone receptor (GHR) in experimental autoimmune encephalomyelitis" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019),
https://hdl.handle.net/21.15107/rcub_ibiss_6006 .

TY  - CONF
AU  - Milošević, Katarina
AU  - Lavrnja, Irena
AU  - Janjić, Marija
AU  - Božić, Iva
AU  - Laketa, Danijela
AU  - Dacić, Sanja
AU  - Peković, Sanja
AU  - Savić, Danijela
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6004
AB  - Traumatic brain injury triggers neuroinflammatory response mediated by distinct populations of myeloid cells, including central nervous system (CNS) resident macrophages - microglia. Depending on the time upon insult this response may either contribute to restorative effects or hinder CNS repair.
Therefore, the focus of this study was on determining temporal course in gene expression profiles of markers specific to the mononuclear phagocyte system (MPS).
We have used the model of cortical stab injury which was performed on 3-months-old male Wistar rats. All animals were divided into 3 experimental groups: control, sham and lesion group and sacrificed at 1, 2, 3 and 7 days post-injury. After brain isolation, mRNA was extracted from cortical pieces around the center of lesion (the same tissue part was used for sham and control groups). The gene expression was analyzed by real-time PCR.
The mRNA levels of Itgam, Aif-1, Cd68 and Cx3Cr1, which are surface markers of MPS, were increased in first two days after brain injury, and then all, except Cd68, showed declining trend compared to control group. Furthermore, we analyzed expression of Arg-1, Il-6 and Tnf-alpha genes, which could be indicators of pro- or anti-inflammatory milieu. All of them increased significantly in the first two days post-injury, and then returned to control level, with the most prominent changes detected in Arg-1 mRNA level.
This study indicates enhanced MPS response in the acute phase after cortical stab injury. Further studies are required to determine which populations of CNS myeloid cells predominate in specific time point upon injury.
PB  - Belgrade : Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Mononuclear Phagocyte System In Traumatic Brain Injury
SP  - 503
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6004
ER  - 

@conference{
author = "Milošević, Katarina and Lavrnja, Irena and Janjić, Marija and Božić, Iva and Laketa, Danijela and Dacić, Sanja and Peković, Sanja and Savić, Danijela",
year = "2019",
abstract = "Traumatic brain injury triggers neuroinflammatory response mediated by distinct populations of myeloid cells, including central nervous system (CNS) resident macrophages - microglia. Depending on the time upon insult this response may either contribute to restorative effects or hinder CNS repair.
Therefore, the focus of this study was on determining temporal course in gene expression profiles of markers specific to the mononuclear phagocyte system (MPS).
We have used the model of cortical stab injury which was performed on 3-months-old male Wistar rats. All animals were divided into 3 experimental groups: control, sham and lesion group and sacrificed at 1, 2, 3 and 7 days post-injury. After brain isolation, mRNA was extracted from cortical pieces around the center of lesion (the same tissue part was used for sham and control groups). The gene expression was analyzed by real-time PCR.
The mRNA levels of Itgam, Aif-1, Cd68 and Cx3Cr1, which are surface markers of MPS, were increased in first two days after brain injury, and then all, except Cd68, showed declining trend compared to control group. Furthermore, we analyzed expression of Arg-1, Il-6 and Tnf-alpha genes, which could be indicators of pro- or anti-inflammatory milieu. All of them increased significantly in the first two days post-injury, and then returned to control level, with the most prominent changes detected in Arg-1 mRNA level.
This study indicates enhanced MPS response in the acute phase after cortical stab injury. Further studies are required to determine which populations of CNS myeloid cells predominate in specific time point upon injury.",
publisher = "Belgrade : Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Mononuclear Phagocyte System In Traumatic Brain Injury",
pages = "503",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6004"
}

Milošević, K., Lavrnja, I., Janjić, M., Božić, I., Laketa, D., Dacić, S., Peković, S.,& Savić, D.. (2019). Mononuclear Phagocyte System In Traumatic Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade : Serbian Neuroscience Society., 503.
https://hdl.handle.net/21.15107/rcub_ibiss_6004

Milošević K, Lavrnja I, Janjić M, Božić I, Laketa D, Dacić S, Peković S, Savić D. Mononuclear Phagocyte System In Traumatic Brain Injury. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:503.
https://hdl.handle.net/21.15107/rcub_ibiss_6004 .

Milošević, Katarina, Lavrnja, Irena, Janjić, Marija, Božić, Iva, Laketa, Danijela, Dacić, Sanja, Peković, Sanja, Savić, Danijela, "Mononuclear Phagocyte System In Traumatic Brain Injury" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):503,
https://hdl.handle.net/21.15107/rcub_ibiss_6004 .

TY  - JOUR
AU  - Božić, Iva
AU  - Savić, Danijela
AU  - Milošević, Ana
AU  - Janjić, Marija
AU  - Laketa, Danijela
AU  - Milošević, Katarina
AU  - Bjelobaba, Ivana
AU  - Jakovljević, Marija
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5874
AB  - Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.
PB  - New York: Springer
T2  - Neurochemical Research
T1  - The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis
IS  - 12
VL  - 44
DO  - 10.1007/s11064-019-02892-4
SP  - 2733
EP  - 2745
ER  - 

@article{
author = "Božić, Iva and Savić, Danijela and Milošević, Ana and Janjić, Marija and Laketa, Danijela and Milošević, Katarina and Bjelobaba, Ivana and Jakovljević, Marija and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2019",
abstract = "Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript and protein expression in the male rat spinal cord during different stages of EAE. Our results reveal a decrease of Kv1.5 transcript and protein level at the peak of disease, where massive infiltration of myeloid cells occurs, together with reactive astrogliosis and demyelination. Also, we revealed that the presence of this channel is not found in infiltrating macrophages/microglia during EAE. It is interesting to note that Kv1.5 channel is expressed only in resting microglia in the naïve animals. Predominant expression of Kv1.5 channel was found in the astrocytes in all experimental groups, while some vimentin+ cells, resembling macrophages, are devoid of Kv1.5 expression. Our results point to the possible link between Kv1.5 channel and the pathophysiological processes in EAE.",
publisher = "New York: Springer",
journal = "Neurochemical Research",
title = "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis",
number = "12",
volume = "44",
doi = "10.1007/s11064-019-02892-4",
pages = "2733-2745"
}

Božić, I., Savić, D., Milošević, A., Janjić, M., Laketa, D., Milošević, K., Bjelobaba, I., Jakovljević, M., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2019). The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research
New York: Springer., 44(12), 2733-2745.
https://doi.org/10.1007/s11064-019-02892-4

Božić I, Savić D, Milošević A, Janjić M, Laketa D, Milošević K, Bjelobaba I, Jakovljević M, Nedeljković N, Peković S, Lavrnja I. The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis. in Neurochemical Research. 2019;44(12):2733-2745.
doi:10.1007/s11064-019-02892-4 .

Božić, Iva, Savić, Danijela, Milošević, Ana, Janjić, Marija, Laketa, Danijela, Milošević, Katarina, Bjelobaba, Ivana, Jakovljević, Marija, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "The Potassium Channel Kv1.5 Expression Alters During Experimental  Autoimmune Encephalomyelitis" in Neurochemical Research, 44, no. 12 (2019):2733-2745,
https://doi.org/10.1007/s11064-019-02892-4 . .

TY  - JOUR
AU  - Božić, Iva
AU  - Milošević, Katarina
AU  - Laketa, Danijela
AU  - Adžić, Marija
AU  - Jakovljević, Marija
AU  - Bjelobaba, Ivana
AU  - Savić, Danijela
AU  - Nedeljković, Nadežda
AU  - Peković, Sanja
AU  - Lavrnja, Irena
PY  - 2018
UR  - http://link.springer.com/10.1007/s11064-018-2509-8
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3027
AB  - Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.
T2  - Neurochemical Research
T1  - Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.
IS  - 5
VL  - 43
DO  - 10.1007/s11064-018-2509-8
SP  - 1020
EP  - 1034
ER  - 

@article{
author = "Božić, Iva and Milošević, Katarina and Laketa, Danijela and Adžić, Marija and Jakovljević, Marija and Bjelobaba, Ivana and Savić, Danijela and Nedeljković, Nadežda and Peković, Sanja and Lavrnja, Irena",
year = "2018",
abstract = "Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1.3 increased by several folds at the peak of EAE at both gene and protein level. Double immunofluorescence analyses demonstrated localization of Kv1.3 on activated microglia, macrophages, and reactive astrocytes around inflammatory lesions. In vitro experiments showed that pharmacological block of Kv1.3 in activated astrocytes suppresses the expression of proinflammatory mediators, suggesting a role of this channel in inflammation. Our results support the hypothesis that Kv1.3 may be a therapeutic target of interest for MS and add astrocytes to the list of cells whose activation would be suppressed by inhibiting Kv1.3 in inflammatory conditions.",
journal = "Neurochemical Research",
title = "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.",
number = "5",
volume = "43",
doi = "10.1007/s11064-018-2509-8",
pages = "1020-1034"
}

Božić, I., Milošević, K., Laketa, D., Adžić, M., Jakovljević, M., Bjelobaba, I., Savić, D., Nedeljković, N., Peković, S.,& Lavrnja, I.. (2018). Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research, 43(5), 1020-1034.
https://doi.org/10.1007/s11064-018-2509-8

Božić I, Milošević K, Laketa D, Adžić M, Jakovljević M, Bjelobaba I, Savić D, Nedeljković N, Peković S, Lavrnja I. Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis.. in Neurochemical Research. 2018;43(5):1020-1034.
doi:10.1007/s11064-018-2509-8 .

Božić, Iva, Milošević, Katarina, Laketa, Danijela, Adžić, Marija, Jakovljević, Marija, Bjelobaba, Ivana, Savić, Danijela, Nedeljković, Nadežda, Peković, Sanja, Lavrnja, Irena, "Voltage Gated Potassium Channel Kv1.3 Is Upregulated on Activated Astrocytes in Experimental Autoimmune Encephalomyelitis." in Neurochemical Research, 43, no. 5 (2018):1020-1034,
https://doi.org/10.1007/s11064-018-2509-8 . .

TY  - JOUR
AU  - Lavrnja, Irena
AU  - Smiljanić, Kosara
AU  - Savić, Danijela
AU  - Mladenović, Aleksandra
AU  - Milošević, Katarina
AU  - Kanazir, Selma
AU  - Peković, Sanja
PY  - 2017
UR  - http://www.nature.com/articles/s41598-017-02638-8
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2760
AB  - Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.
T2  - Scientific Reports
T1  - Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord
IS  - 1
VL  - 7
DO  - 10.1038/s41598-017-02638-8
SP  - 2702
EP  - 2702
ER  - 

@article{
author = "Lavrnja, Irena and Smiljanić, Kosara and Savić, Danijela and Mladenović, Aleksandra and Milošević, Katarina and Kanazir, Selma and Peković, Sanja",
year = "2017",
abstract = "Increased evidence suggests that dysregulation of cholesterol metabolism may be a key event contributing to progression of multiple sclerosis (MS). Using an experimental autoimmune encephalomyelitis (EAE) model of MS we revealed specific changes in the mRNA and protein expression of key molecules involved in the maintaining of cholesterol homeostasis in the rat spinal cord: 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46A1) during the course of disease. The presence of myelin lipid debris was seen only at the peak of EAE in demyelination loci being efficiently removed during the recovery period. Since CYP46A1 is responsible for removal of cholesterol excess, we performed a detailed profiling of CYP46A1 expression and revealed regional and temporal specificities in its distribution. Double immunofluorescence staining demonstrated CYP46A1 localization with neurons, infiltrated macrophages, microglia and astrocytes in the areas of demyelination, suggesting that these cells play a role in cholesterol turnover in EAE. We propose that alterations in the regulation of cholesterol metabolism at the onset and peak of EAE may add to the progression of disease, while during the recovery period may have beneficial effects contributing to the regeneration of myelin sheath and restoration of neuronal function.",
journal = "Scientific Reports",
title = "Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord",
number = "1",
volume = "7",
doi = "10.1038/s41598-017-02638-8",
pages = "2702-2702"
}

Lavrnja, I., Smiljanić, K., Savić, D., Mladenović, A., Milošević, K., Kanazir, S.,& Peković, S.. (2017). Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord. in Scientific Reports, 7(1), 2702-2702.
https://doi.org/10.1038/s41598-017-02638-8

Lavrnja I, Smiljanić K, Savić D, Mladenović A, Milošević K, Kanazir S, Peković S. Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord. in Scientific Reports. 2017;7(1):2702-2702.
doi:10.1038/s41598-017-02638-8 .

Lavrnja, Irena, Smiljanić, Kosara, Savić, Danijela, Mladenović, Aleksandra, Milošević, Katarina, Kanazir, Selma, Peković, Sanja, "Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord" in Scientific Reports, 7, no. 1 (2017):2702-2702,
https://doi.org/10.1038/s41598-017-02638-8 . .