Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease
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Аутори
Aranđelović, JovanaSantrač, Anja
Batinić, Bojan
Todorović, Lidija
Ahmed Khan, Md Zubair
Rashid, Farjana
Poe, Michael M.
Obradović, Aleksandar
Cook, James M.
Savić, Miroslav M.
Чланак у часопису (Објављена верзија)
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© 2021 IOS Press
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Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced ...a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.
Кључне речи:
5xFAD / Alzheimer's disease / Emotionality / Motivation / Motor function / Negative allosteric modulation / Positive allosteric modulation / α5 GABAAreceptorsИзвор:
Journal of Alzheimer's Disease, 2021, 84, 3, 1291-1302Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
- National Institutes of Health (NIH) - USA [DA-043204]
- National Institutes of Health (NIH) - USA [R01NS076517]
- National Science Foundation, Division of Chemistry [CHE-1625735]
DOI: 10.3233/JAD-215079
ISSN: 1387-2877
PubMed: 34657887
WoS: 000722640800031
Scopus: 2-s2.0-85120474181
Колекције
Институција/група
VinčaTY - JOUR AU - Aranđelović, Jovana AU - Santrač, Anja AU - Batinić, Bojan AU - Todorović, Lidija AU - Ahmed Khan, Md Zubair AU - Rashid, Farjana AU - Poe, Michael M. AU - Obradović, Aleksandar AU - Cook, James M. AU - Savić, Miroslav M. PY - 2021 UR - https://vinar.vin.bg.ac.rs/handle/123456789/10072 AB - Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising. T2 - Journal of Alzheimer's Disease T1 - Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease VL - 84 IS - 3 SP - 1291 EP - 1302 DO - 10.3233/JAD-215079 ER -
@article{ author = "Aranđelović, Jovana and Santrač, Anja and Batinić, Bojan and Todorović, Lidija and Ahmed Khan, Md Zubair and Rashid, Farjana and Poe, Michael M. and Obradović, Aleksandar and Cook, James M. and Savić, Miroslav M.", year = "2021", abstract = "Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising.", journal = "Journal of Alzheimer's Disease", title = "Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease", volume = "84", number = "3", pages = "1291-1302", doi = "10.3233/JAD-215079" }
Aranđelović, J., Santrač, A., Batinić, B., Todorović, L., Ahmed Khan, M. Z., Rashid, F., Poe, M. M., Obradović, A., Cook, J. M.,& Savić, M. M.. (2021). Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease. in Journal of Alzheimer's Disease, 84(3), 1291-1302. https://doi.org/10.3233/JAD-215079
Aranđelović J, Santrač A, Batinić B, Todorović L, Ahmed Khan MZ, Rashid F, Poe MM, Obradović A, Cook JM, Savić MM. Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease. in Journal of Alzheimer's Disease. 2021;84(3):1291-1302. doi:10.3233/JAD-215079 .
Aranđelović, Jovana, Santrač, Anja, Batinić, Bojan, Todorović, Lidija, Ahmed Khan, Md Zubair, Rashid, Farjana, Poe, Michael M., Obradović, Aleksandar, Cook, James M., Savić, Miroslav M., "Positive and Negative Selective Allosteric Modulators of α5 GABAA Receptors: Effects on Emotionality, Motivation, and Motor Function in the 5xFAD Model of Alzheimer’s Disease" in Journal of Alzheimer's Disease, 84, no. 3 (2021):1291-1302, https://doi.org/10.3233/JAD-215079 . .