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 . .