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  - Piantadosi, Sean C.
AU  - French, Beverly J.
AU  - Poe, Michael M.
AU  - Timić, Tamara
AU  - Marković, Bojan
AU  - Pabba, Mohan
AU  - Seney, Marianne L.
AU  - Oh, Hyunjung
AU  - Orser, Beverley A.
AU  - Savić, Miroslav
AU  - Cook, James M.
AU  - Sibille, Etienne
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2633
AB  - Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
PB  - Frontiers Media Sa, Lausanne
T2  - Frontiers in Pharmacology
T1  - Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator
VL  - 7
DO  - 10.3389/fphar.2016.00446
ER  - 

@article{
author = "Piantadosi, Sean C. and French, Beverly J. and Poe, Michael M. and Timić, Tamara and Marković, Bojan and Pabba, Mohan and Seney, Marianne L. and Oh, Hyunjung and Orser, Beverley A. and Savić, Miroslav and Cook, James M. and Sibille, Etienne",
year = "2016",
abstract = "Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Pharmacology",
title = "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator",
volume = "7",
doi = "10.3389/fphar.2016.00446"
}

Piantadosi, S. C., French, B. J., Poe, M. M., Timić, T., Marković, B., Pabba, M., Seney, M. L., Oh, H., Orser, B. A., Savić, M., Cook, J. M.,& Sibille, E.. (2016). Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator. in Frontiers in Pharmacology
Frontiers Media Sa, Lausanne., 7.
https://doi.org/10.3389/fphar.2016.00446

Piantadosi SC, French BJ, Poe MM, Timić T, Marković B, Pabba M, Seney ML, Oh H, Orser BA, Savić M, Cook JM, Sibille E. Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator. in Frontiers in Pharmacology. 2016;7.
doi:10.3389/fphar.2016.00446 .

Piantadosi, Sean C., French, Beverly J., Poe, Michael M., Timić, Tamara, Marković, Bojan, Pabba, Mohan, Seney, Marianne L., Oh, Hyunjung, Orser, Beverley A., Savić, Miroslav, Cook, James M., Sibille, Etienne, "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator" in Frontiers in Pharmacology, 7 (2016),
https://doi.org/10.3389/fphar.2016.00446 . .