Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats

Neuropharmacology
Ivica GranicVolker Nimmrich

Abstract

Amyloid-beta (Abeta) is toxic to neurons and such toxicity is - at least in part - mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. The present study reveals that inhibition of calpain is also neuroprotective in an in vivo model of Abeta oligomer-induced neurodegeneration in rats. Abeta-induced lesions of the nucleus basalis induced a significant decrease in the number of cholinergic neurons and their projecting fibers, as determined by analysis of choline-acetyltransferase in the nucleus basalis magnocellularis and cortical mantle of the lesioned animals. Treatment with the calpain inhibitor A-705253 significantly attenuated cholinergic neurodegeneration in a dose-dependent manner. Calpain inhibition also significantly diminished the accompanying neuroinflammatory response, as determined by immunohistochemical analysis of microglia activation. Administration of beta-amyloid markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dos...Continue Reading

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Citations

Sep 17, 2015·Journal of Neurochemistry·Anna WilkaniecAgata Adamczyk
Apr 9, 2011·Progress in Neurobiology·Joao P Lopes, Paula Agostinho
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Feb 6, 2020·Expert Opinion on Drug Discovery·Levente Endre DókusZoltán Bánóczi
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