TY  - JOUR
AU  - Đorović, Đorđe
AU  - Lazarević, Vesna
AU  - Aranđelović, Jovana
AU  - Stevanović, Vladimir
AU  - Paslawski, Wojciech
AU  - Zhang, Xiaoqun
AU  - Velimirović, Milica
AU  - Petronijević, Nataša
AU  - Puškaš, Laslo
AU  - Savić, Miroslav
AU  - Svenningsson, Per
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5503
AB  - Background: Early life stress is a major risk factor for later development of psychiatric disorders, including post-traumatic stress disorder (PTSD). An intricate relationship exists between various neurotransmitters (such as glutamate, norepinephrine or serotonin), calcium/calmodulin-dependent protein kinase II (CaMKII), as an important regulator of glutamatergic synaptic function, and PTSD. Here, we developed a double-hit model to investigate the interaction of maternal deprivation (MD) as an early life stress model and single prolonged stress (SPS) as a PTSD model at the behavioral and molecular levels. Methods: Male Wistar rats exposed to these stress paradigms were subjected to a comprehensive behavioral analysis. In hippocampal synaptosomes we investigated neurotransmitter release and glutamate concentration. The expression of CaMKII and the content of monoamines were determined in selected brain regions. Brain-derived neurotrophic factor (BDNF) mRNA was quantified by radioactive in situ hybridization. Results: We report a distinct behavioral phenotype in the double-hit group. Double-hit and SPS groups had decreased hippocampal presynaptic glutamatergic function. In hippocampus, double-hit stress caused a decrease in autophosphorylation of CaMKII. In prefrontal cortex, both SPS and double-hit stress had a similar effect on CaMKII autophosphorylation. Double-hit stress, rather than SPS, affected the norepinephrine and serotonin levels in prefrontal cortex, and suppressed BDNF gene expression in prefrontal cortex and hippocampus. Limitations: The study was conducted in male rats only. The affected brain regions cannot be restricted to hippocampus, prefrontal cortex and amygdala. Conclusion: Double-hit stress caused more pronounced and distinct behavioral, molecular and functional changes, compared to MD or SPS alone.
PB  - Elsevier B.V.
T2  - Journal of Affective Disorders
T1  - Maternal deprivation causes CaMKII downregulation and modulates glutamate, norepinephrine and serotonin in limbic brain areas in a rat model of single prolonged stress
VL  - 349
SP  - 286
EP  - 296
DO  - 10.1016/j.jad.2024.01.087
ER  - 

@article{
author = "Đorović, Đorđe and Lazarević, Vesna and Aranđelović, Jovana and Stevanović, Vladimir and Paslawski, Wojciech and Zhang, Xiaoqun and Velimirović, Milica and Petronijević, Nataša and Puškaš, Laslo and Savić, Miroslav and Svenningsson, Per",
year = "2024",
abstract = "Background: Early life stress is a major risk factor for later development of psychiatric disorders, including post-traumatic stress disorder (PTSD). An intricate relationship exists between various neurotransmitters (such as glutamate, norepinephrine or serotonin), calcium/calmodulin-dependent protein kinase II (CaMKII), as an important regulator of glutamatergic synaptic function, and PTSD. Here, we developed a double-hit model to investigate the interaction of maternal deprivation (MD) as an early life stress model and single prolonged stress (SPS) as a PTSD model at the behavioral and molecular levels. Methods: Male Wistar rats exposed to these stress paradigms were subjected to a comprehensive behavioral analysis. In hippocampal synaptosomes we investigated neurotransmitter release and glutamate concentration. The expression of CaMKII and the content of monoamines were determined in selected brain regions. Brain-derived neurotrophic factor (BDNF) mRNA was quantified by radioactive in situ hybridization. Results: We report a distinct behavioral phenotype in the double-hit group. Double-hit and SPS groups had decreased hippocampal presynaptic glutamatergic function. In hippocampus, double-hit stress caused a decrease in autophosphorylation of CaMKII. In prefrontal cortex, both SPS and double-hit stress had a similar effect on CaMKII autophosphorylation. Double-hit stress, rather than SPS, affected the norepinephrine and serotonin levels in prefrontal cortex, and suppressed BDNF gene expression in prefrontal cortex and hippocampus. Limitations: The study was conducted in male rats only. The affected brain regions cannot be restricted to hippocampus, prefrontal cortex and amygdala. Conclusion: Double-hit stress caused more pronounced and distinct behavioral, molecular and functional changes, compared to MD or SPS alone.",
publisher = "Elsevier B.V.",
journal = "Journal of Affective Disorders",
title = "Maternal deprivation causes CaMKII downregulation and modulates glutamate, norepinephrine and serotonin in limbic brain areas in a rat model of single prolonged stress",
volume = "349",
pages = "286-296",
doi = "10.1016/j.jad.2024.01.087"
}

Đorović, Đ., Lazarević, V., Aranđelović, J., Stevanović, V., Paslawski, W., Zhang, X., Velimirović, M., Petronijević, N., Puškaš, L., Savić, M.,& Svenningsson, P.. (2024). Maternal deprivation causes CaMKII downregulation and modulates glutamate, norepinephrine and serotonin in limbic brain areas in a rat model of single prolonged stress. in Journal of Affective Disorders
Elsevier B.V.., 349, 286-296.
https://doi.org/10.1016/j.jad.2024.01.087

Đorović Đ, Lazarević V, Aranđelović J, Stevanović V, Paslawski W, Zhang X, Velimirović M, Petronijević N, Puškaš L, Savić M, Svenningsson P. Maternal deprivation causes CaMKII downregulation and modulates glutamate, norepinephrine and serotonin in limbic brain areas in a rat model of single prolonged stress. in Journal of Affective Disorders. 2024;349:286-296.
doi:10.1016/j.jad.2024.01.087 .

Đorović, Đorđe, Lazarević, Vesna, Aranđelović, Jovana, Stevanović, Vladimir, Paslawski, Wojciech, Zhang, Xiaoqun, Velimirović, Milica, Petronijević, Nataša, Puškaš, Laslo, Savić, Miroslav, Svenningsson, Per, "Maternal deprivation causes CaMKII downregulation and modulates glutamate, norepinephrine and serotonin in limbic brain areas in a rat model of single prolonged stress" in Journal of Affective Disorders, 349 (2024):286-296,
https://doi.org/10.1016/j.jad.2024.01.087 . .

TY  - CONF
AU  - Aranđelović, Jovana
AU  - Kojić, Jana
AU  - Mirković, Kristina
AU  - Jančić, Ivan
AU  - Todorović, Lidija
AU  - Savić, Miroslav
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5520
AB  - Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.
PB  - European College of Neuropsychopharmacology (ECNP)
C3  - 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
T1  - Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5520
ER  - 

@conference{
author = "Aranđelović, Jovana and Kojić, Jana and Mirković, Kristina and Jančić, Ivan and Todorović, Lidija and Savić, Miroslav",
year = "2023",
abstract = "Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation.",
publisher = "European College of Neuropsychopharmacology (ECNP)",
journal = "36th ECPN congress, 7th -10th October 2023, Barcelona, Spain",
title = "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5520"
}

Aranđelović, J., Kojić, J., Mirković, K., Jančić, I., Todorović, L.,& Savić, M.. (2023). Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain
European College of Neuropsychopharmacology (ECNP)..
https://hdl.handle.net/21.15107/rcub_farfar_5520

Aranđelović J, Kojić J, Mirković K, Jančić I, Todorović L, Savić M. Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats. in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_5520 .

Aranđelović, Jovana, Kojić, Jana, Mirković, Kristina, Jančić, Ivan, Todorović, Lidija, Savić, Miroslav, "Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats" in 36th ECPN congress, 7th -10th October 2023, Barcelona, Spain (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5520 .

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  - Aranđelović, Jovana
AU  - Santrač, Anja
AU  - Batinić, Bojan
AU  - Todorović, Lidija
AU  - Stevanović, Vladimir
AU  - Tiruveedhula, Veera Venkata Naga Phani Babu
AU  - Sharmin, Dishary
AU  - Rashid, Farjana
AU  - Stanojević, Boban
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4203
AB  - Aims: GABAergic modulation involved in cognitive processing appears to be substan- tially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABA A receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods: After 10-day treatment with PAM, NAM, or solvent, 6-month-old trans- genic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results: PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non- transgenic males. NAM treatment declined social interaction in transgenic and non- transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion: PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with promi- nent neuroinflammation.
PB  - John Wiley and Sons Inc
T2  - CNS Neuroscience & Therapeutics
T1  - Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease
VL  - 28
IS  - 11
SP  - 1767
EP  - 1778
DO  - 10.1111/cns.13914
ER  - 

@article{
author = "Aranđelović, Jovana and Santrač, Anja and Batinić, Bojan and Todorović, Lidija and Stevanović, Vladimir and Tiruveedhula, Veera Venkata Naga Phani Babu and Sharmin, Dishary and Rashid, Farjana and Stanojević, Boban and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Aims: GABAergic modulation involved in cognitive processing appears to be substan- tially changed in Alzheimer's disease (AD). In a widely used 5xFAD model of AD, we aimed to assess if negative and positive allosteric modulators of α5 GABA A receptors (NAM and PAM, respectively) would affect social interaction, social, object and spatial memory, and neuroinflammation. Methods: After 10-day treatment with PAM, NAM, or solvent, 6-month-old trans- genic and non-transgenic 5xFAD mice underwent testing in a behavioral battery. Gene expressions of IL-1β, IL-6, TNF-α, GFAP, and IBA-1 were determined in hippocampus and prefrontal cortex by qPCR. Results: PAM treatment impaired spatial learning in transgenic females compared to solvent-treated transgenic females, and social recognition in transgenic and non- transgenic males. NAM treatment declined social interaction in transgenic and non- transgenic males, while had beneficial effect on cognitive flexibility in non-transgenic males compared to solvent-treated non-transgenic males. Transgenic animals have not fully displayed cognitive symptoms, but neuroinflammation was confirmed. NAM reduced proinflammatory gene expressions in transgenic females and astrogliosis in transgenic males compared to pathological controls. Conclusion: PAM and NAM failed to exert favorable behavioral effects in transgenic animals. Suppression of neuroinflammation obtained with NAM calls for more studies with GABAergic ligands in amyloid beta- and/or tau-dependent models with promi- nent neuroinflammation.",
publisher = "John Wiley and Sons Inc",
journal = "CNS Neuroscience & Therapeutics",
title = "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease",
volume = "28",
number = "11",
pages = "1767-1778",
doi = "10.1111/cns.13914"
}

Aranđelović, J., Santrač, A., Batinić, B., Todorović, L., Stevanović, V., Tiruveedhula, V. V. N. P. B., Sharmin, D., Rashid, F., Stanojević, B., Cook, J.,& Savić, M.. (2022). Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics
John Wiley and Sons Inc., 28(11), 1767-1778.
https://doi.org/10.1111/cns.13914

Aranđelović J, Santrač A, Batinić B, Todorović L, Stevanović V, Tiruveedhula VVNPB, Sharmin D, Rashid F, Stanojević B, Cook J, Savić M. Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease. in CNS Neuroscience & Therapeutics. 2022;28(11):1767-1778.
doi:10.1111/cns.13914 .

Aranđelović, Jovana, Santrač, Anja, Batinić, Bojan, Todorović, Lidija, Stevanović, Vladimir, Tiruveedhula, Veera Venkata Naga Phani Babu, Sharmin, Dishary, Rashid, Farjana, Stanojević, Boban, Cook, James, Savić, Miroslav, "Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease" in CNS Neuroscience & Therapeutics, 28, no. 11 (2022):1767-1778,
https://doi.org/10.1111/cns.13914 . .

TY  - JOUR
AU  - Santrač, Anja
AU  - Bijelić, Dunja
AU  - Stevanović, Vladimir
AU  - Banićević, Marija
AU  - Aranđelović, Jovana
AU  - Batinić, Bojan
AU  - Sharmin, Dishary
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4071
AB  - Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activ- ity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate ani- mals themselves. Behavioral results were mirrored in GABA switch and spontane- ous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner.
PB  - John Wiley and Sons Inc
T2  - Autism Research
T1  - Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner
DO  - 10.1002/aur.2699
ER  - 

@article{
author = "Santrač, Anja and Bijelić, Dunja and Stevanović, Vladimir and Banićević, Marija and Aranđelović, Jovana and Batinić, Bojan and Sharmin, Dishary and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP-III-022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP-III-022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activ- ity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP-III-022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP-III-022 elicited certain changes in control animals similar to those manifested in valproate ani- mals themselves. Behavioral results were mirrored in GABA switch and spontane- ous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex-specific manner.",
publisher = "John Wiley and Sons Inc",
journal = "Autism Research",
title = "Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner",
doi = "10.1002/aur.2699"
}

Santrač, A., Bijelić, D., Stevanović, V., Banićević, M., Aranđelović, J., Batinić, B., Sharmin, D., Cook, J.,& Savić, M.. (2022). Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner. in Autism Research
John Wiley and Sons Inc..
https://doi.org/10.1002/aur.2699

Santrač A, Bijelić D, Stevanović V, Banićević M, Aranđelović J, Batinić B, Sharmin D, Cook J, Savić M. Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner. in Autism Research. 2022;.
doi:10.1002/aur.2699 .

Santrač, Anja, Bijelić, Dunja, Stevanović, Vladimir, Banićević, Marija, Aranđelović, Jovana, Batinić, Bojan, Sharmin, Dishary, Cook, James, Savić, Miroslav, "Postweaning positive modulation of α5GABAA receptors improves autism-like features in prenatal valproate rat model in a sex-specific manner" in Autism Research (2022),
https://doi.org/10.1002/aur.2699 . .

TY  - JOUR
AU  - Santrač, Anja
AU  - Batinić, Bojan
AU  - Timić-Stamenić, Tamara
AU  - Aranđelović, Jovana
AU  - Sharmin, Dishary
AU  - Knutson, Daniel E.
AU  - Cook, James
AU  - Savić, Miroslav
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3968
AB  - Positive allosteric modulators (PAMs) of α5GABAA receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.
PB  - Elsevier B.V.
T2  - Behavioural Brain Research
T1  - Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus
VL  - 416
DO  - 10.1016/j.bbr.2021.113578
ER  - 

@article{
author = "Santrač, Anja and Batinić, Bojan and Timić-Stamenić, Tamara and Aranđelović, Jovana and Sharmin, Dishary and Knutson, Daniel E. and Cook, James and Savić, Miroslav",
year = "2022",
abstract = "Positive allosteric modulators (PAMs) of α5GABAA receptors (α5GABAARs) are emerging as potential therapeutics for a range of neuropsychiatric disorders. However, their role in memory processing of healthy animals is not sufficiently examined. We tested the effects of MP-III-022 (1 mg/kg, 2.5 mg/kg and 10 mg/kg), a PAM known to be selective for α5GABAARs and devoid of prominent side-effects, in different behavioral paradigms (Morris water maze, novel object recognition test and social novelty discrimination) and on GABRA5 expression in Wistar rats, 30 min and 24 h after intraperitoneal treatment administration. The lowest dose tested worsened short-term object memory. The same dose, administered two times in a span of 24 h, improved spatial and impaired object and, at a trend level, social memory. The highest dose had a detrimental effect on all types of long-term memory (object memory at a trend level) and short-term spatial memory, but improved short-term object and social memory. Distinct sets of expression changes were detected in both prefrontal cortex and two regions of the hippocampus, but the latter ones could be assessed as more consequential. An increase of GABRA5 mRNA in CA2 occurred in parallel with improvement of object and social, but impairment of spatial memory, while the opposite happened with a trend level change in CA1. Our study demonstrates the variability of the roles of the α5GABAAR based on its level of expression and localization, in dependence on the type and protocol of cognitive tasks, as well as the respective timing of pharmacological modulation and testing.",
publisher = "Elsevier B.V.",
journal = "Behavioural Brain Research",
title = "Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus",
volume = "416",
doi = "10.1016/j.bbr.2021.113578"
}

Santrač, A., Batinić, B., Timić-Stamenić, T., Aranđelović, J., Sharmin, D., Knutson, D. E., Cook, J.,& Savić, M.. (2022). Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus. in Behavioural Brain Research
Elsevier B.V.., 416.
https://doi.org/10.1016/j.bbr.2021.113578

Santrač A, Batinić B, Timić-Stamenić T, Aranđelović J, Sharmin D, Knutson DE, Cook J, Savić M. Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus. in Behavioural Brain Research. 2022;416.
doi:10.1016/j.bbr.2021.113578 .

Santrač, Anja, Batinić, Bojan, Timić-Stamenić, Tamara, Aranđelović, Jovana, Sharmin, Dishary, Knutson, Daniel E., Cook, James, Savić, Miroslav, "Positive modulation of α5GABAA receptors leads to dichotomous effects in rats on memory pattern and GABRA5 expression in prefrontal cortex and hippocampus" in Behavioural Brain Research, 416 (2022),
https://doi.org/10.1016/j.bbr.2021.113578 . .

TY  - THES
AU  - Aranđelović, Jovana
PY  - 2022
UR  - https://eteze.bg.ac.rs/application/showtheses?thesesId=9095
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:29380/bdef:Content/download
UR  - https://plus.cobiss.net/cobiss/sr/sr/bib/77009673
UR  - https://nardus.mpn.gov.rs/handle/123456789/21433
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4968
AB  - Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu,objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju,ekspresiju subjedinica GABAA receptora i neuroinflamaciju.Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki.U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom.
AB  - Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotionalityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.
PB  - Универзитет у Београду, Фармацеутски факултет
T2  - Универзитет у Београду
T1  - Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti
UR  - https://hdl.handle.net/21.15107/rcub_nardus_21433
ER  - 

@phdthesis{
author = "Aranđelović, Jovana",
year = "2022",
abstract = "Ciljevi: Postoje dokazi da je GABAergička modulacija uključena u kognitivne proceseznačajno promenjena kod Alchajmerove bolesti (AD). U široko korišćenom 5xFADmodelu AD, želeli smo da procenimo da li negativni i pozitivni alosterni modulatori α5GABAA receptora (NAM i PAM, respektivno) utiču na socijalnu interakciju, socijalnu,objektnu i prostornu memoriju, senzomotornu funkciju, emocionalnost, motivaciju,ekspresiju subjedinica GABAA receptora i neuroinflamaciju.Metode: Posle produžene primene PAM, NAM ili rastvarača, 6 meseci stari transgeni inetransgeni 5xFAD miševi podvrgnuti su testiranju u bihejvioralnoj bateriji. Ekspresijegena za Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap i Iba1 određene su u hipokampusui prefrontalnom korteksu pomoću qPCR metode.Rezultati: PAM tretman narušio je prostorno učenje kod transgenih ženki, socijalnoprepoznavanje kod transgenih i netransgenih mužjaka i motornu funkciju kod transgenihmužjaka. NAM tretman je smanjio socijalnu interakciju kod transgenih i netransgenihmužjaka i emocionalnost kod transgenih mužjaka. NAM je imao povoljan efekat nakognitivnu fleksibilnost kod netransgenih mužjaka. U hipokampusu, oba tretmana su vratilana normalne nivoe recipročne promene u ekspresiji Gabra2 i Gabra3 kod transgenih ženki.U prefrontalnom korteksu, PAM je smanjio Gabra5 kod oba pola, dok je NAM povećaoGabra2 kod transgenih mužjaka. Transgene životinje nisu u potpunosti razvile kognitivnesimptome, ali je potvrđena neuroinflamacija. NAM je smanjio ekspresiju proinflamatornihgena kod transgenih ženki i astroglioze kod transgenih mužjaka.Zaključak: PAM i NAM nisu uspeli da ispolje konzistentno povoljne bihejvioralne efektekod transgenih životinja. Supresija neuroinflamacije dobijena NAM-om zahteva višestudija sa GABAergičkim ligandima u amiloidnim beta- i/ili tau-zavisnim modelima saizraženom neuroinflamacijom., Aims: GABAergic modulation involved in cognitive processing appears to be substantiallychanged in Alzheimer’s disease (AD). In a widely used 5xFAD model of AD, we aimed toassess if negative and positive allosteric modulators of α5 GABAA receptors (NAM andPAM, respectively) would affect social interaction, social, object and spatial memory,sensorimotor function, emotionality, motivation, expression of GABAA receptor subunitsand neuroinflammation.Methods: After protracted treatment with PAM, NAM or solvent, 6-month-old transgenicand non-transgenic 5xFAD mice underwent testing in a behavioral battery. Geneexpressions of Gabra2, Gabra3, Gabra5, Il1b, Il-6, Tnfa, Gfap and Iba1 were determinedin hippocampus and prefrontal cortex by qPCR analysis.Results: PAM treatment impaired spatial learning in transgenic females, and socialrecognition and motor function in both transgenic and non-transgenic males and intransgenic males, respectively. NAM treatment declined social interaction and emotionalityin both transgenic and non-transgenic males and transgenic males, respectively. NAM had abeneficial effect on cognitive flexibility in non-transgenic males. In hippocampus, bothtreatments reversed reciprocal Gabra2 and Gabra3 changes in transgenic females. Inprefrontal cortex, PAM decreased Gabra5 in both genders, while NAM increased Gabra2in transgenic males. Transgenic animals have not fully displayed cognitive symptoms,while neuroinflammation was confirmed. NAM reduced proinflammatory gene expressionsin transgenic females and astrogliosis in transgenic males.Conclusion: PAM and NAM failed to exert consistently favorable behavioral effects intransgenic animals. Suppression of neuroinflammation obtained with NAM calls for morestudies with GABAergic ligands in amyloid beta- and/or tau-dependent models withprominent neuroinflammation.",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti",
url = "https://hdl.handle.net/21.15107/rcub_nardus_21433"
}

Aranđelović, J.. (2022). Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti. in Универзитет у Београду
Универзитет у Београду, Фармацеутски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_21433

Aranđelović J. Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti. in Универзитет у Београду. 2022;.
https://hdl.handle.net/21.15107/rcub_nardus_21433 .

Aranđelović, Jovana, "Bimodalna modulacija alfa5 GABAA receptora u eksperimentalnom modelu Alchajmerove bolesti" in Универзитет у Београду (2022),
https://hdl.handle.net/21.15107/rcub_nardus_21433 .

TY  - JOUR
AU  - Đoković, Jelena
AU  - Savić, Sanela
AU  - Mitrović, Jelena
AU  - Nikolić, Ines
AU  - Marković, Bojan
AU  - Ranđelović, Danijela
AU  - Antić-Stanković, Jelena
AU  - Božić, Dragana
AU  - Cekić, Nebojša
AU  - Stevanović, Vladimir
AU  - Batinić, Bojan
AU  - Aranđelović, Jovana
AU  - Savić, Miroslav
AU  - Savić, Snežana
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5541
AB  - The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of −40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078–0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.
PB  - MDPI
T2  - International Journal of Molecular Sciences
T1  - Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats
VL  - 22
IS  - 15
DO  - 10.3390/ijms22157991
ER  - 

@article{
author = "Đoković, Jelena and Savić, Sanela and Mitrović, Jelena and Nikolić, Ines and Marković, Bojan and Ranđelović, Danijela and Antić-Stanković, Jelena and Božić, Dragana and Cekić, Nebojša and Stevanović, Vladimir and Batinić, Bojan and Aranđelović, Jovana and Savić, Miroslav and Savić, Snežana",
year = "2021",
abstract = "The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of −40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078–0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.",
publisher = "MDPI",
journal = "International Journal of Molecular Sciences",
title = "Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats",
volume = "22",
number = "15",
doi = "10.3390/ijms22157991"
}

Đoković, J., Savić, S., Mitrović, J., Nikolić, I., Marković, B., Ranđelović, D., Antić-Stanković, J., Božić, D., Cekić, N., Stevanović, V., Batinić, B., Aranđelović, J., Savić, M.,& Savić, S.. (2021). Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats. in International Journal of Molecular Sciences
MDPI., 22(15).
https://doi.org/10.3390/ijms22157991

Đoković J, Savić S, Mitrović J, Nikolić I, Marković B, Ranđelović D, Antić-Stanković J, Božić D, Cekić N, Stevanović V, Batinić B, Aranđelović J, Savić M, Savić S. Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats. in International Journal of Molecular Sciences. 2021;22(15).
doi:10.3390/ijms22157991 .

Đoković, Jelena, Savić, Sanela, Mitrović, Jelena, Nikolić, Ines, Marković, Bojan, Ranđelović, Danijela, Antić-Stanković, Jelena, Božić, Dragana, Cekić, Nebojša, Stevanović, Vladimir, Batinić, Bojan, Aranđelović, Jovana, Savić, Miroslav, Savić, Snežana, "Curcumin loaded pegylated nanoemulsions designed for maintained antioxidant effects and improved bioavailability: A pilot study on rats" in International Journal of Molecular Sciences, 22, no. 15 (2021),
https://doi.org/10.3390/ijms22157991 . .