TY  - JOUR
AU  - Vasović, Dolika D.
AU  - Ivković, Sanja
AU  - Živanović, Ana
AU  - Major, Tamara
AU  - Milašin, Jelena M.
AU  - Nikolić, Nađa S.
AU  - Simonović, Jelena
AU  - Šutulović, Nikola
AU  - Hrnčić, Dragan
AU  - Stanojlović, Olivera
AU  - Vesković, Milena
AU  - Rašić, Dejan M.
AU  - Mladenović, Dušan
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5611
AB  - Diabetic retinopathy is not cured efficiently and changes of lifestyle measures may delay early retinal injury in
diabetes. The aim of our study was to investigate the effects of reduced daily light exposure on retinal vascular
changes in streptozotocin (STZ)-induced model of DM with emphasis on inflammation, Aqp4 expression, visual
cycle and cholesterol metabolism-related gene expression in rat retina and RPE. Male Wistar rats were divided
into the following groups: 1. control; 2. diabetic group (DM) treated with streptozotocin (100 mg/kg); 3. group
exposed to light/dark cycle 6/18 h (6/18); 4. diabetic group exposed to light/dark cycle 6/18 h (DM+6/18).
Retinal vascular abnormalities were estimated based on lectin staining, while the expression of genes involved in
the visual cycle, cholesterol metabolism, and inflammation was determined by qRT-PCR. Reduced light exposure
alleviated vasculopathy, gliosis and the expression of IL-1 and TNF-α in the retina with increased perivascular
Aqp4 expression. The expression of genes involved in visual cycle and cholesterol metabolism was significantly
up-regulated in RPE in DM+6/18 vs. DM group. In the retina only the expression of APOE was significantly
higher in DM+6/18 vs. DM group. Reduced light exposure mitigates vascular changes and gliosis in DM via its
anti-inflammatory effect, increased retinal cholesterol turnover and perivascular Aqp4 expression.
PB  - Elsevier
T2  - Chemico-Biological Interactions
T1  - Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover
VL  - 394
SP  - 110996
DO  - 10.1016/j.cbi.2024.110996
ER  - 

@article{
author = "Vasović, Dolika D. and Ivković, Sanja and Živanović, Ana and Major, Tamara and Milašin, Jelena M. and Nikolić, Nađa S. and Simonović, Jelena and Šutulović, Nikola and Hrnčić, Dragan and Stanojlović, Olivera and Vesković, Milena and Rašić, Dejan M. and Mladenović, Dušan",
year = "2024",
abstract = "Diabetic retinopathy is not cured efficiently and changes of lifestyle measures may delay early retinal injury in
diabetes. The aim of our study was to investigate the effects of reduced daily light exposure on retinal vascular
changes in streptozotocin (STZ)-induced model of DM with emphasis on inflammation, Aqp4 expression, visual
cycle and cholesterol metabolism-related gene expression in rat retina and RPE. Male Wistar rats were divided
into the following groups: 1. control; 2. diabetic group (DM) treated with streptozotocin (100 mg/kg); 3. group
exposed to light/dark cycle 6/18 h (6/18); 4. diabetic group exposed to light/dark cycle 6/18 h (DM+6/18).
Retinal vascular abnormalities were estimated based on lectin staining, while the expression of genes involved in
the visual cycle, cholesterol metabolism, and inflammation was determined by qRT-PCR. Reduced light exposure
alleviated vasculopathy, gliosis and the expression of IL-1 and TNF-α in the retina with increased perivascular
Aqp4 expression. The expression of genes involved in visual cycle and cholesterol metabolism was significantly
up-regulated in RPE in DM+6/18 vs. DM group. In the retina only the expression of APOE was significantly
higher in DM+6/18 vs. DM group. Reduced light exposure mitigates vascular changes and gliosis in DM via its
anti-inflammatory effect, increased retinal cholesterol turnover and perivascular Aqp4 expression.",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover",
volume = "394",
pages = "110996",
doi = "10.1016/j.cbi.2024.110996"
}

Vasović, D. D., Ivković, S., Živanović, A., Major, T., Milašin, J. M., Nikolić, N. S., Simonović, J., Šutulović, N., Hrnčić, D., Stanojlović, O., Vesković, M., Rašić, D. M.,& Mladenović, D.. (2024). Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover. in Chemico-Biological Interactions
Elsevier., 394, 110996.
https://doi.org/10.1016/j.cbi.2024.110996

Vasović DD, Ivković S, Živanović A, Major T, Milašin JM, Nikolić NS, Simonović J, Šutulović N, Hrnčić D, Stanojlović O, Vesković M, Rašić DM, Mladenović D. Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover. in Chemico-Biological Interactions. 2024;394:110996.
doi:10.1016/j.cbi.2024.110996 .

Vasović, Dolika D., Ivković, Sanja, Živanović, Ana, Major, Tamara, Milašin, Jelena M., Nikolić, Nađa S., Simonović, Jelena, Šutulović, Nikola, Hrnčić, Dragan, Stanojlović, Olivera, Vesković, Milena, Rašić, Dejan M., Mladenović, Dušan, "Reduced light exposure mitigates streptozotocin-induced vascular changes and gliosis in diabetic retina by an anti-inflammatory effect and increased retinal cholesterol turnover" in Chemico-Biological Interactions, 394 (2024):110996,
https://doi.org/10.1016/j.cbi.2024.110996 . .

TY  - JOUR
AU  - Jovanović Macura, Irena
AU  - Živanović, Ana
AU  - Perović, Milka
AU  - Ćirić, Jelena
AU  - Major, Tamara
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5121
AB  - Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer’s disease (AD). The increased accumulation of Aβ is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The Aβ accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 M and 12 M 5xFAD and 12 M WT retinas. The increase in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 M WT retinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiological (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease
VL  - 24
IS  - 18
DO  - 10.3390/ijms241814092
ER  - 

@article{
author = "Jovanović Macura, Irena and Živanović, Ana and Perović, Milka and Ćirić, Jelena and Major, Tamara and Kanazir, Selma and Ivković, Sanja",
year = "2023",
abstract = "Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer’s disease (AD). The increased accumulation of Aβ is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The Aβ accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 M and 12 M 5xFAD and 12 M WT retinas. The increase in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 M WT retinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiological (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease",
volume = "24",
number = "18",
doi = "10.3390/ijms241814092"
}

Jovanović Macura, I., Živanović, A., Perović, M., Ćirić, J., Major, T., Kanazir, S.,& Ivković, S.. (2023). The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease. in International Journal of Molecular Sciences
MDPI., 24(18).
https://doi.org/10.3390/ijms241814092

Jovanović Macura I, Živanović A, Perović M, Ćirić J, Major T, Kanazir S, Ivković S. The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease. in International Journal of Molecular Sciences. 2023;24(18).
doi:10.3390/ijms241814092 .

Jovanović Macura, Irena, Živanović, Ana, Perović, Milka, Ćirić, Jelena, Major, Tamara, Kanazir, Selma, Ivković, Sanja, "The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer’s Disease" in International Journal of Molecular Sciences, 24, no. 18 (2023),
https://doi.org/10.3390/ijms241814092 . .

TY  - JOUR
AU  - Jovanović-Macura, Irena
AU  - Đuričić, Ivana
AU  - Major, Tamara
AU  - Milanović, Desanka
AU  - Šobajić, Slađana
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5543
AB  - Introduction: During fetal development, the proper development of neural and visual systems relies on the maternal supplementation of omega-3 fatty acids through placental transfer. Pregnant women are strongly advised to augment their diet with additional sources of omega-3, such as fish oil (FO). This supplementation has been linked to a reduced risk of preterm birth, pre-eclampsia, and perinatal depression. Recently, higher doses of omega-3 supplementation have been recommended for pregnant women. Considering that omega-3 fatty acids, particularly docosahexaenoic acid (DHA), play a crucial role in maintaining the delicate homeostasis required for the proper functioning of the retina and photoreceptors the effects of high-dose fish oil (FO) supplementation during pregnancy and lactation on the retina and retinal pigmented epithelium (RPE) in healthy offspring warrant better understanding. Methods: The fatty acid content and the changes in the expression of the genes regulating cholesterol homeostasis and DHA transport in the retina and RPE were evaluated following the high-dose FO supplementation. Results: Our study demonstrated that despite the high-dose FO treatment during pregnancy and lactation, the rigorous DHA homeostasis in the retina and RPE of the two-month-old offspring remained balanced. Another significant finding of this study is the increase in the expression levels of major facilitator superfamily domain-containing protein (Mfsd2a), a primary DHA transporter. Mfsd2a also serves as a major regulator of transcytosis during development, and a reduction in Mfsd2a levels poses a major risk for the development of leaky blood vessels. Conclusion: Impairment of the blood-retinal barrier (BRB) is associated with the development of numerous ocular diseases, and a better understanding of how to manipulate transcytosis in the BRB during development can enhance drug delivery through the BRB or contribute to the repair of central nervous system (CNS) barriers.
PB  - Frontiers Media SA
T2  - Frontiers in Nutrition
T1  - The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring
VL  - 10
SP  - 1330414
DO  - 10.3389/fnut.2023.1330414
ER  - 

@article{
author = "Jovanović-Macura, Irena and Đuričić, Ivana and Major, Tamara and Milanović, Desanka and Šobajić, Slađana and Kanazir, Selma and Ivković, Sanja",
year = "2023",
abstract = "Introduction: During fetal development, the proper development of neural and visual systems relies on the maternal supplementation of omega-3 fatty acids through placental transfer. Pregnant women are strongly advised to augment their diet with additional sources of omega-3, such as fish oil (FO). This supplementation has been linked to a reduced risk of preterm birth, pre-eclampsia, and perinatal depression. Recently, higher doses of omega-3 supplementation have been recommended for pregnant women. Considering that omega-3 fatty acids, particularly docosahexaenoic acid (DHA), play a crucial role in maintaining the delicate homeostasis required for the proper functioning of the retina and photoreceptors the effects of high-dose fish oil (FO) supplementation during pregnancy and lactation on the retina and retinal pigmented epithelium (RPE) in healthy offspring warrant better understanding. Methods: The fatty acid content and the changes in the expression of the genes regulating cholesterol homeostasis and DHA transport in the retina and RPE were evaluated following the high-dose FO supplementation. Results: Our study demonstrated that despite the high-dose FO treatment during pregnancy and lactation, the rigorous DHA homeostasis in the retina and RPE of the two-month-old offspring remained balanced. Another significant finding of this study is the increase in the expression levels of major facilitator superfamily domain-containing protein (Mfsd2a), a primary DHA transporter. Mfsd2a also serves as a major regulator of transcytosis during development, and a reduction in Mfsd2a levels poses a major risk for the development of leaky blood vessels. Conclusion: Impairment of the blood-retinal barrier (BRB) is associated with the development of numerous ocular diseases, and a better understanding of how to manipulate transcytosis in the BRB during development can enhance drug delivery through the BRB or contribute to the repair of central nervous system (CNS) barriers.",
publisher = "Frontiers Media SA",
journal = "Frontiers in Nutrition",
title = "The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring",
volume = "10",
pages = "1330414",
doi = "10.3389/fnut.2023.1330414"
}

Jovanović-Macura, I., Đuričić, I., Major, T., Milanović, D., Šobajić, S., Kanazir, S.,& Ivković, S.. (2023). The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring. in Frontiers in Nutrition
Frontiers Media SA., 10, 1330414.
https://doi.org/10.3389/fnut.2023.1330414

Jovanović-Macura I, Đuričić I, Major T, Milanović D, Šobajić S, Kanazir S, Ivković S. The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring. in Frontiers in Nutrition. 2023;10:1330414.
doi:10.3389/fnut.2023.1330414 .

Jovanović-Macura, Irena, Đuričić, Ivana, Major, Tamara, Milanović, Desanka, Šobajić, Slađana, Kanazir, Selma, Ivković, Sanja, "The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring" in Frontiers in Nutrition, 10 (2023):1330414,
https://doi.org/10.3389/fnut.2023.1330414 . .

TY  - JOUR
AU  - Martinović, Jelena
AU  - Samardžić, Janko
AU  - Zarić Kontić, Marina
AU  - Ivković, Sanja
AU  - Dacić, Sanja
AU  - Major, Tamara
AU  - Radosavljević, Milica
AU  - Švob Štrac, Dubravka
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5407
AB  - Zaleplon is a positive allosteric modulator of the γ-aminobutyric acid (GABA)A receptor approved for the short-term treatment of insomnia. Previous publications on zaleplon have not addressed the proteins involved in its mechanism of action but have mostly referred to behavioral or pharmacological studies. Since both GABAergic and glutamatergic signaling have been shown to regulate wakefulness and sleep, we examined the effects of prolonged zaleplon treatment (0.625 mg/kg for 5 days) on these systems in the hippocampus of male Wistar rats. Western blot and immunohistochemical analyses showed that the upregulated components of GABAergic signaling (glutamate decarboxylase, vesicular GABA transporter, GABA, and α1 subunit of the GABAA receptor) were accompanied by increased protein levels in the glutamatergic system (vesicular glutamate transporter 1 and NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptor). Our results, showing that zaleplon enhances GABA neurotransmission in the hippocampus, were not surprising. However, we found that treatment also increased glutamatergic signaling. This could be the result of the downregulation of adenosine A1 receptors, important modulators of the glutamatergic system. Further studies are needed to investigate the effects of the zaleplon-induced increase in hippocampal glutamatergic neurotransmission and the possible involvement of the adenosine system in zaleplon’s mechanism of action.
PB  - MDPI
T2  - Brain Sciences
T1  - Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus
VL  - 13
IS  - 12
DO  - 10.3390/brainsci13121707
ER  - 

@article{
author = "Martinović, Jelena and Samardžić, Janko and Zarić Kontić, Marina and Ivković, Sanja and Dacić, Sanja and Major, Tamara and Radosavljević, Milica and Švob Štrac, Dubravka",
year = "2023",
abstract = "Zaleplon is a positive allosteric modulator of the γ-aminobutyric acid (GABA)A receptor approved for the short-term treatment of insomnia. Previous publications on zaleplon have not addressed the proteins involved in its mechanism of action but have mostly referred to behavioral or pharmacological studies. Since both GABAergic and glutamatergic signaling have been shown to regulate wakefulness and sleep, we examined the effects of prolonged zaleplon treatment (0.625 mg/kg for 5 days) on these systems in the hippocampus of male Wistar rats. Western blot and immunohistochemical analyses showed that the upregulated components of GABAergic signaling (glutamate decarboxylase, vesicular GABA transporter, GABA, and α1 subunit of the GABAA receptor) were accompanied by increased protein levels in the glutamatergic system (vesicular glutamate transporter 1 and NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptor). Our results, showing that zaleplon enhances GABA neurotransmission in the hippocampus, were not surprising. However, we found that treatment also increased glutamatergic signaling. This could be the result of the downregulation of adenosine A1 receptors, important modulators of the glutamatergic system. Further studies are needed to investigate the effects of the zaleplon-induced increase in hippocampal glutamatergic neurotransmission and the possible involvement of the adenosine system in zaleplon’s mechanism of action.",
publisher = "MDPI",
journal = "Brain Sciences",
title = "Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus",
volume = "13",
number = "12",
doi = "10.3390/brainsci13121707"
}

Martinović, J., Samardžić, J., Zarić Kontić, M., Ivković, S., Dacić, S., Major, T., Radosavljević, M.,& Švob Štrac, D.. (2023). Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus. in Brain Sciences
MDPI., 13(12).
https://doi.org/10.3390/brainsci13121707

Martinović J, Samardžić J, Zarić Kontić M, Ivković S, Dacić S, Major T, Radosavljević M, Švob Štrac D. Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus. in Brain Sciences. 2023;13(12).
doi:10.3390/brainsci13121707 .

Martinović, Jelena, Samardžić, Janko, Zarić Kontić, Marina, Ivković, Sanja, Dacić, Sanja, Major, Tamara, Radosavljević, Milica, Švob Štrac, Dubravka, "Prolonged Zaleplon Treatment Increases the Expression of Proteins Involved in GABAergic and Glutamatergic Signaling in the Rat Hippocampus" in Brain Sciences, 13, no. 12 (2023),
https://doi.org/10.3390/brainsci13121707 . .

TY  - CONF
AU  - Mirković, Kristina
AU  - Aranđelović, Jovana
AU  - Kojić, Jana
AU  - Stevanović, Vladimir
AU  - Batinić, Bojan
AU  - Todorović, Vanja
AU  - Đoković, Jelena
AU  - Santrač, Anja
AU  - Major, Tamara
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5521
AB  - Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker.
PB  - European College of Neuropsychopharmacology (ECNP)
C3  - 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
T1  - Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5521
ER  - 

@conference{
author = "Mirković, Kristina and Aranđelović, Jovana and Kojić, Jana and Stevanović, Vladimir and Batinić, Bojan and Todorović, Vanja and Đoković, Jelena and Santrač, Anja and Major, Tamara and Savić, Miroslav",
year = "2023",
abstract = "Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker.",
publisher = "European College of Neuropsychopharmacology (ECNP)",
journal = "36th ECPN congress, 7th -10th October 2023, Barcelona, Spain",
title = "Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5521"
}

Mirković, K., Aranđelović, J., Kojić, J., Stevanović, V., Batinić, B., Todorović, V., Đoković, J., Santrač, A., Major, T.,& Savić, M.. (2023). Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
European College of Neuropsychopharmacology (ECNP)..
https://hdl.handle.net/21.15107/rcub_farfar_5521

Mirković K, Aranđelović J, Kojić J, Stevanović V, Batinić B, Todorović V, Đoković J, Santrač A, Major T, Savić M. Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5521 .

Mirković, Kristina, Aranđelović, Jovana, Kojić, Jana, Stevanović, Vladimir, Batinić, Bojan, Todorović, Vanja, Đoković, Jelena, Santrač, Anja, Major, Tamara, Savić, Miroslav, "Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats" in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5521 .

TY  - JOUR
AU  - Jovanović Macura, Irena
AU  - Đuričić, Ivana
AU  - Major, Tamara
AU  - Milanović, Desanka
AU  - Brkić, Marjana
AU  - Šobajić, Slađana
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4309
AB  - The recommended fish oil (FO) supplementation doses often yield low omega-3 polyunsaturated fatty acids (PUFAs) tissue bioavailability, and higher doses (up to 10 g per day) have been increasingly recommended. However, the exact effects of such FO supplementation on the healthy retina and retinal pigmented epithelium (RPE) are unknown. Our study showed that the high dose FO treatment did not imbalance the rigorous docosahexaenoic acid (DHA, C22:6n3) homeostasis in the retina and RPE in the three-month-old female B6/SLJ mice. Instead, we have found the significant increase in the expression of Mfsd2a, the main DHA transporter. Mfsd2a is also an essential regulator of blood vessel transcytosis and the decrease in Mfsd2a expression can be a risk factor for developing leaky blood vessels. Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of the retinal blood vessels.
PB  - Elsevier Ltd
T2  - Journal of Functional Foods
T1  - The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice
VL  - 99
DO  - 10.1016/j.jff.2022.105302
ER  - 

@article{
author = "Jovanović Macura, Irena and Đuričić, Ivana and Major, Tamara and Milanović, Desanka and Brkić, Marjana and Šobajić, Slađana and Kanazir, Selma and Ivković, Sanja",
year = "2022",
abstract = "The recommended fish oil (FO) supplementation doses often yield low omega-3 polyunsaturated fatty acids (PUFAs) tissue bioavailability, and higher doses (up to 10 g per day) have been increasingly recommended. However, the exact effects of such FO supplementation on the healthy retina and retinal pigmented epithelium (RPE) are unknown. Our study showed that the high dose FO treatment did not imbalance the rigorous docosahexaenoic acid (DHA, C22:6n3) homeostasis in the retina and RPE in the three-month-old female B6/SLJ mice. Instead, we have found the significant increase in the expression of Mfsd2a, the main DHA transporter. Mfsd2a is also an essential regulator of blood vessel transcytosis and the decrease in Mfsd2a expression can be a risk factor for developing leaky blood vessels. Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of the retinal blood vessels.",
publisher = "Elsevier Ltd",
journal = "Journal of Functional Foods",
title = "The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice",
volume = "99",
doi = "10.1016/j.jff.2022.105302"
}

Jovanović Macura, I., Đuričić, I., Major, T., Milanović, D., Brkić, M., Šobajić, S., Kanazir, S.,& Ivković, S.. (2022). The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice. in Journal of Functional Foods
Elsevier Ltd., 99.
https://doi.org/10.1016/j.jff.2022.105302

Jovanović Macura I, Đuričić I, Major T, Milanović D, Brkić M, Šobajić S, Kanazir S, Ivković S. The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice. in Journal of Functional Foods. 2022;99.
doi:10.1016/j.jff.2022.105302 .

Jovanović Macura, Irena, Đuričić, Ivana, Major, Tamara, Milanović, Desanka, Brkić, Marjana, Šobajić, Slađana, Kanazir, Selma, Ivković, Sanja, "The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice" in Journal of Functional Foods, 99 (2022),
https://doi.org/10.1016/j.jff.2022.105302 . .

TY  - JOUR
AU  - Ivković, Sanja
AU  - Major, Tamara
AU  - Mitić, Miloš
AU  - Lončarević-Vasiljković, Nataša
AU  - Jović, Milena
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4078
AB  - The brain is the softest organ in the body, and any change in the mechanical properties of the tissue induces the activation of glial cells, astrocytes and microglia. Amyloid plaques, one of the main pathological features of Alzheimer's disease (AD), are substantially harder than the surrounding brain tissue and can activate astrocytes and microglia resulting in the glial engulfment of plaques. Durotaxis, a migratory preference towards stiffer tissue, is prompting microglia to form a mechanical barrier around plaques reducing amyloid β (Aβ) induced neurotoxicity. Mechanoreceptors are highly expressed in the brain, particularly in microglia. The large increase in the expression of the mechanoreceptor Piezo1 was observed in the brains from AD animal models and AD patients in plaque encompassing glia. Importantly, Piezo1 function is regulated via force-from–lipids through the lipid composition of the membrane and membranous incorporation of polyunsaturated fatty acids (PUFAs) can affect the function of Piezo1 altering mechanosensitive properties of the cell. On the other hand, PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and immune response and Piezo1 activity was implicated in the similar modulations of microglia behavior. Finally, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1. Further studies are needed to elucidate the connection between PUFAs, Piezo1 expression, and microglia behavior in the AD brain. These findings could open new possibilities in harnessing microglia in AD and in developing novel therapeutic strategies.
PB  - Elsevier Inc.
T2  - Life Sciences
T1  - Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease
VL  - 297
DO  - 10.1016/j.lfs.2022.120470
ER  - 

@article{
author = "Ivković, Sanja and Major, Tamara and Mitić, Miloš and Lončarević-Vasiljković, Nataša and Jović, Milena and Adžić, Miroslav",
year = "2022",
abstract = "The brain is the softest organ in the body, and any change in the mechanical properties of the tissue induces the activation of glial cells, astrocytes and microglia. Amyloid plaques, one of the main pathological features of Alzheimer's disease (AD), are substantially harder than the surrounding brain tissue and can activate astrocytes and microglia resulting in the glial engulfment of plaques. Durotaxis, a migratory preference towards stiffer tissue, is prompting microglia to form a mechanical barrier around plaques reducing amyloid β (Aβ) induced neurotoxicity. Mechanoreceptors are highly expressed in the brain, particularly in microglia. The large increase in the expression of the mechanoreceptor Piezo1 was observed in the brains from AD animal models and AD patients in plaque encompassing glia. Importantly, Piezo1 function is regulated via force-from–lipids through the lipid composition of the membrane and membranous incorporation of polyunsaturated fatty acids (PUFAs) can affect the function of Piezo1 altering mechanosensitive properties of the cell. On the other hand, PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and immune response and Piezo1 activity was implicated in the similar modulations of microglia behavior. Finally, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1. Further studies are needed to elucidate the connection between PUFAs, Piezo1 expression, and microglia behavior in the AD brain. These findings could open new possibilities in harnessing microglia in AD and in developing novel therapeutic strategies.",
publisher = "Elsevier Inc.",
journal = "Life Sciences",
title = "Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease",
volume = "297",
doi = "10.1016/j.lfs.2022.120470"
}

Ivković, S., Major, T., Mitić, M., Lončarević-Vasiljković, N., Jović, M.,& Adžić, M.. (2022). Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease. in Life Sciences
Elsevier Inc.., 297.
https://doi.org/10.1016/j.lfs.2022.120470

Ivković S, Major T, Mitić M, Lončarević-Vasiljković N, Jović M, Adžić M. Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease. in Life Sciences. 2022;297.
doi:10.1016/j.lfs.2022.120470 .

Ivković, Sanja, Major, Tamara, Mitić, Miloš, Lončarević-Vasiljković, Nataša, Jović, Milena, Adžić, Miroslav, "Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease" in Life Sciences, 297 (2022),
https://doi.org/10.1016/j.lfs.2022.120470 . .