An 5 GABAA Receptor Inverse Agonist, 5IA, Attenuates Amyloid Beta-Induced Neuronal Death in Mouse Hippocampal Cultures.

Show simple item record Vinnakota, Chitra en Govindpani, Karan en Tate, Warren Perry en Peppercorn, Katie en Anekal, Praju Vikas en Waldvogel, Henry en Faull, Richard en Kwakowsky, Andrea en 2020-07-08T04:45:26Z en 2020-05-06 en
dc.identifier.citation International journal of molecular sciences 21(9) 06 May 2020 en
dc.identifier.issn 1422-0067 en
dc.identifier.uri en
dc.description.abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which no cognition-restoring therapies exist. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Increasing evidence suggests a remodeling of the GABAergic system in AD, which might represent an important therapeutic target. An inverse agonist of 5 subunit-containing GABAA receptors (α5GABAARs), 3-(5-Methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3-a]phthalazine (5IA) has cognition-enhancing properties. This study aimed to characterize the effects of 5IA on amyloid beta (A1-42)-induced molecular and cellular changes. Mouse primary hippocampal cultures were exposed to either A1-42 alone, or 5IA alone, 5IA with A1-42 or vehicle alone, and changes in cell viability and mRNA expression of several GABAergic signaling components were assessed. Treatment with 100 nM of 5IA reduced A1-42-induced cell loss by 23.8% (p < 0.0001) after 6 h and by 17.3% after 5 days of treatment (p < 0.0001). Furthermore, we observed an A1-42-induced increase in ambient GABA levels, as well as upregulated mRNA expression of the GABAAR α2,α5,2/3 subunits and the GABABR R1 and R2 subunits. Such changes in GABARs expression could potentially disrupt inhibitory neurotransmission and normal network activity. Treatment with 5IA restored A1-42-induced changes in the expression of α5GABAARs. In summary, this compound might hold neuroprotective potential and represent a new therapeutic avenue for AD. en
dc.format.medium Electronic en
dc.language eng en
dc.relation.ispartofseries International journal of molecular sciences en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.title An 5 GABAA Receptor Inverse Agonist, 5IA, Attenuates Amyloid Beta-Induced Neuronal Death in Mouse Hippocampal Cultures. en
dc.type Journal Article en
dc.identifier.doi 10.3390/ijms21093284 en
pubs.issue 9 en
pubs.volume 21 en
dc.rights.holder Copyright: The authors en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 802651 en Medical and Health Sciences en Medical Sciences en Anatomy and Medical Imaging en
dc.identifier.eissn 1422-0067 en
pubs.record-created-at-source-date 2020-05-10 en
pubs.dimensions-id 32384683 en

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