Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress
Само за регистроване кориснике
2022
Аутори
Bernardo, AshleyLee, Philip
Marcotte, Michael
Mian, Md Yeunus
Rezvanian, Sepideh
Sharmin, Dishary
Kovačević, Aleksandra
Savić, Miroslav
Cook, James M.
Sibille, Etienne
Prevot, Thomas D.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 confir...m 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.
Извор:
Neuropsychopharmacology, 2022, 47, 9, 1608-1619Издавач:
- Springer Nature
Финансирање / пројекти:
- Chemistry synthesis funded by NIH (DA-043204, R01NS076517) to JMC
- NanoCellEmoCog - Neuroimmune aspects of mood, anxiety and cognitive effects of leads/drug candidates acting at GABAA and/or sigma-2 receptors: In vitro/in vivo delineation by nano- and hiPSC-based platform (RS-ScienceFundRS-Ideje-7749108)
DOI: 10.1038/s41386-022-01360-y
ISSN: 0893-133X
PubMed: 35701547
WoS: 000810867300004
Scopus: 2-s2.0-85131811863
Институција/група
PharmacyTY - 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 . .