TY  - JOUR
AU  - Bernardo, Ashley
AU  - Lee, Philip
AU  - Marcotte, Michael
AU  - Mian, Md Yeunus
AU  - Rezvanian, Sepideh
AU  - Sharmin, Dishary
AU  - Kovačević, Aleksandra
AU  - Savić, Miroslav
AU  - Cook, James M.
AU  - Sibille, Etienne
AU  - Prevot, Thomas D.
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5540
AB  - Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.
PB  - Springer Nature
T2  - Neuropsychopharmacology
T1  - Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress
VL  - 47
IS  - 9
SP  - 1608
EP  - 1619
DO  - 10.1038/s41386-022-01360-y
ER  - 

@article{
author = "Bernardo, Ashley and Lee, Philip and Marcotte, Michael and Mian, Md Yeunus and Rezvanian, Sepideh and Sharmin, Dishary and Kovačević, Aleksandra and Savić, Miroslav and Cook, James M. and Sibille, Etienne and Prevot, Thomas D.",
year = "2022",
abstract = "Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.",
publisher = "Springer Nature",
journal = "Neuropsychopharmacology",
title = "Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress",
volume = "47",
number = "9",
pages = "1608-1619",
doi = "10.1038/s41386-022-01360-y"
}

Bernardo, A., Lee, P., Marcotte, M., Mian, M. Y., Rezvanian, S., Sharmin, D., Kovačević, A., Savić, M., Cook, J. M., Sibille, E.,& Prevot, T. D.. (2022). Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. in Neuropsychopharmacology
Springer Nature., 47(9), 1608-1619.
https://doi.org/10.1038/s41386-022-01360-y

Bernardo A, Lee P, Marcotte M, Mian MY, Rezvanian S, Sharmin D, Kovačević A, Savić M, Cook JM, Sibille E, Prevot TD. Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. in Neuropsychopharmacology. 2022;47(9):1608-1619.
doi:10.1038/s41386-022-01360-y .

Bernardo, Ashley, Lee, Philip, Marcotte, Michael, Mian, Md Yeunus, Rezvanian, Sepideh, Sharmin, Dishary, Kovačević, Aleksandra, Savić, Miroslav, Cook, James M., Sibille, Etienne, Prevot, Thomas D., "Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress" in Neuropsychopharmacology, 47, no. 9 (2022):1608-1619,
https://doi.org/10.1038/s41386-022-01360-y . .

TY  - JOUR
AU  - Batinić, Bojan
AU  - Santrač, Anja
AU  - Jančić, Ivan
AU  - Li, Guanguan
AU  - Vidojević, Aleksandra
AU  - Marković, Bojan
AU  - Cook, James M.
AU  - Savić, Miroslav
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2821
AB  - We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.
PB  - Pergamon-Elsevier Science Ltd, Oxford
T2  - International Journal of Developmental Neuroscience
T1  - Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide
VL  - 61
SP  - 31
EP  - 39
DO  - 10.1016/j.ijdevneu.2017.06.001
ER  - 

@article{
author = "Batinić, Bojan and Santrač, Anja and Jančić, Ivan and Li, Guanguan and Vidojević, Aleksandra and Marković, Bojan and Cook, James M. and Savić, Miroslav",
year = "2017",
abstract = "We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.",
publisher = "Pergamon-Elsevier Science Ltd, Oxford",
journal = "International Journal of Developmental Neuroscience",
title = "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide",
volume = "61",
pages = "31-39",
doi = "10.1016/j.ijdevneu.2017.06.001"
}

Batinić, B., Santrač, A., Jančić, I., Li, G., Vidojević, A., Marković, B., Cook, J. M.,& Savić, M.. (2017). Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience
Pergamon-Elsevier Science Ltd, Oxford., 61, 31-39.
https://doi.org/10.1016/j.ijdevneu.2017.06.001

Batinić B, Santrač A, Jančić I, Li G, Vidojević A, Marković B, Cook JM, Savić M. Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience. 2017;61:31-39.
doi:10.1016/j.ijdevneu.2017.06.001 .

Batinić, Bojan, Santrač, Anja, Jančić, Ivan, Li, Guanguan, Vidojević, Aleksandra, Marković, Bojan, Cook, James M., Savić, Miroslav, "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide" in International Journal of Developmental Neuroscience, 61 (2017):31-39,
https://doi.org/10.1016/j.ijdevneu.2017.06.001 . .

TY  - JOUR
AU  - Vidojević, Aleksandra
AU  - Živković, Aleksandra
AU  - Santrač, Anja
AU  - Divović, Branka
AU  - Savić, Miroslav
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2479
AB  - Introduction: Animal models enable the investigation of association between maternal inflammation during pregnancy and different neuropsychiatric disorders in offspring, which has been reported in epidemiological studies. Aim: Investigation of inflammation existence in female rats exposed to LPS during pregnancy and its influence on spatial memory impairment in offspring in Morris water maze. Material and methods: Pregnant Wistar females were exposed to LPS or saline (SAL) at gestational day 15 and 16 and their blood was taken for TNF-α concentration determination. Rats of both sexes (male - M, female - F) went through five-day memory acquisition and one-day memory retrieval test during two periods (35 - 39 postnatal day (P35-39) and P40; likewise P55-59 and P60). We analyzed memory acquisition (latency and path efficiency to platform finding and total distance travelled) and memory retrieval parameters (number of entries and path efficiency to first entry to the target zone). Results: We found higher TNF-α concentration present in LPS-treated dams. There were no significant differences for any of the parameters analyzed for P40 animals and P60 females. M/LPS/P60 rats had a significantly decreased path efficiency to platform finding, increased total distance travelled and a trend of increased latency to platform finding, compared to M/SAL/P60 in the memory acquisition test, and a significantly decreased path efficiency to first entry to the target zone in the memory retrieval test. Conclusion: Lipopolysaccharide (LPS) - induced maternal inflammation during pregnancy leads to spatial memory impairment in male rat offspring in early adulthood, a finding that can be a basis for animal modeling of neurodevelopmental disorders.
AB  - Uvod: Animalni modeli pružaju mogućnost ispitivanja veze između zapaljenja kod majki tokom trudnoće i različitih neuropsihijatrijskih poremećaja potomstva, pokazane u epidemiološkim studijama. Cilj rada: U ovom radu je ispitivano postojanje zapaljenja kod ženki pacova izloženih LPS-u tokom trudnoće i njegov uticaj na oštećenje prostorne memorije potomstva u Morisovom vodenom lavirintu. Materijal i metode: Gravidne ženke soja Wistar bile su izložene LPS-u ili fiziološkom rastvoru (SAL) 15. i 16. dana gestacije i uzimana im je krv radi određivanja koncentracije TNF-α. Mladunci oba pola (mužjaci - M, ženke - F) podvrgnuti su petodnevnom testu sticanja i jednodnevnom testu pozivanja memorije u dva postnatalna perioda (35 - 39. postnatalnog dana života (P35- 39) i P40, odnosno P55-59 i P60). Analizirani su parametri sticanja (latencija i efikasnost putanje do pronalaska platforme i ukupan pređeni put) i pozivanja prostorne memorije (broj ulazaka i efikasnost putanje do prvog ulaska u ciljnu zonu). Rezultati: Utvrđene su povišene koncentracije TNF-α kod majki tretiranih LPS-om. Kod P40 životinja nije bilo značajnih razlika u praćenim bihejvioralnim parametrima, kao ni kod P60 ženki. Pokazano je da su pacovi M/LPS/P60 imali statistički značajno manju efikasnost putanje do pronalaska platforme, veći ukupni pređeni put i trend povećanja latencije do pronalaska platforme u odnosu na M/SAL/P60 u testu sticanja memorije, kao i značajno manju efikasnost putanje do prvog ulaska u ciljnu zonu u testu pozivanja memorije. Zaključak: Lipopolisaharidom (LPS) izazvano zapaljenje kod ženki pacova tokom trudnoće utiče na oštećenje prostorne memorije kod potomstva muškog pola u ranom odraslom dobu, što bi moglo poslužiti za razvijanje animalnog modela neurorazvojnih oboljenja.
PB  - Univerzitet u Beogradu - Medicinski fakultet, Beograd
T2  - Medicinski podmladak
T1  - Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće
VL  - 66
IS  - 2
SP  - 37
EP  - 43
DO  - 10.5937/medpodm1502037V
ER  - 

@article{
author = "Vidojević, Aleksandra and Živković, Aleksandra and Santrač, Anja and Divović, Branka and Savić, Miroslav",
year = "2015",
abstract = "Introduction: Animal models enable the investigation of association between maternal inflammation during pregnancy and different neuropsychiatric disorders in offspring, which has been reported in epidemiological studies. Aim: Investigation of inflammation existence in female rats exposed to LPS during pregnancy and its influence on spatial memory impairment in offspring in Morris water maze. Material and methods: Pregnant Wistar females were exposed to LPS or saline (SAL) at gestational day 15 and 16 and their blood was taken for TNF-α concentration determination. Rats of both sexes (male - M, female - F) went through five-day memory acquisition and one-day memory retrieval test during two periods (35 - 39 postnatal day (P35-39) and P40; likewise P55-59 and P60). We analyzed memory acquisition (latency and path efficiency to platform finding and total distance travelled) and memory retrieval parameters (number of entries and path efficiency to first entry to the target zone). Results: We found higher TNF-α concentration present in LPS-treated dams. There were no significant differences for any of the parameters analyzed for P40 animals and P60 females. M/LPS/P60 rats had a significantly decreased path efficiency to platform finding, increased total distance travelled and a trend of increased latency to platform finding, compared to M/SAL/P60 in the memory acquisition test, and a significantly decreased path efficiency to first entry to the target zone in the memory retrieval test. Conclusion: Lipopolysaccharide (LPS) - induced maternal inflammation during pregnancy leads to spatial memory impairment in male rat offspring in early adulthood, a finding that can be a basis for animal modeling of neurodevelopmental disorders., Uvod: Animalni modeli pružaju mogućnost ispitivanja veze između zapaljenja kod majki tokom trudnoće i različitih neuropsihijatrijskih poremećaja potomstva, pokazane u epidemiološkim studijama. Cilj rada: U ovom radu je ispitivano postojanje zapaljenja kod ženki pacova izloženih LPS-u tokom trudnoće i njegov uticaj na oštećenje prostorne memorije potomstva u Morisovom vodenom lavirintu. Materijal i metode: Gravidne ženke soja Wistar bile su izložene LPS-u ili fiziološkom rastvoru (SAL) 15. i 16. dana gestacije i uzimana im je krv radi određivanja koncentracije TNF-α. Mladunci oba pola (mužjaci - M, ženke - F) podvrgnuti su petodnevnom testu sticanja i jednodnevnom testu pozivanja memorije u dva postnatalna perioda (35 - 39. postnatalnog dana života (P35- 39) i P40, odnosno P55-59 i P60). Analizirani su parametri sticanja (latencija i efikasnost putanje do pronalaska platforme i ukupan pređeni put) i pozivanja prostorne memorije (broj ulazaka i efikasnost putanje do prvog ulaska u ciljnu zonu). Rezultati: Utvrđene su povišene koncentracije TNF-α kod majki tretiranih LPS-om. Kod P40 životinja nije bilo značajnih razlika u praćenim bihejvioralnim parametrima, kao ni kod P60 ženki. Pokazano je da su pacovi M/LPS/P60 imali statistički značajno manju efikasnost putanje do pronalaska platforme, veći ukupni pređeni put i trend povećanja latencije do pronalaska platforme u odnosu na M/SAL/P60 u testu sticanja memorije, kao i značajno manju efikasnost putanje do prvog ulaska u ciljnu zonu u testu pozivanja memorije. Zaključak: Lipopolisaharidom (LPS) izazvano zapaljenje kod ženki pacova tokom trudnoće utiče na oštećenje prostorne memorije kod potomstva muškog pola u ranom odraslom dobu, što bi moglo poslužiti za razvijanje animalnog modela neurorazvojnih oboljenja.",
publisher = "Univerzitet u Beogradu - Medicinski fakultet, Beograd",
journal = "Medicinski podmladak",
title = "Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće",
volume = "66",
number = "2",
pages = "37-43",
doi = "10.5937/medpodm1502037V"
}

Vidojević, A., Živković, A., Santrač, A., Divović, B.,& Savić, M.. (2015). Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće. in Medicinski podmladak
Univerzitet u Beogradu - Medicinski fakultet, Beograd., 66(2), 37-43.
https://doi.org/10.5937/medpodm1502037V

Vidojević A, Živković A, Santrač A, Divović B, Savić M. Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće. in Medicinski podmladak. 2015;66(2):37-43.
doi:10.5937/medpodm1502037V .

Vidojević, Aleksandra, Živković, Aleksandra, Santrač, Anja, Divović, Branka, Savić, Miroslav, "Sticanje i pozivanje prostorne memorije kod potomstva ženki pacova izloženih lipopolisaharidom izazvanom zapaljenju tokom trudnoće" in Medicinski podmladak, 66, no. 2 (2015):37-43,
https://doi.org/10.5937/medpodm1502037V . .