Received for publication June 25, 2008.
Revised August 12, 2008.
Accepted for publication August 12, 2008.

Inhibition of calpain prevents NMDA-induced degeneration of the nucleus basalis and associated behavioral dysfunction

Abstract

NMDA receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium dependent cystein protease, has been identified as part of such an NMDA receptor-induced excitotoxic signaling pathway. The present study addressed the question whether inhibition of calpain can prevent neuronal cell death and associated behavioral deficits in a disease-relevant animal model, which is based on excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. Excitotoxic lesions of the nucleus basalis with NMDA induced a markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dose-dependently prevented the behavioral deficit. Subsequent analysis of choline acetyltransferase in the cortical mantle of the lesioned animals revealed that application of A-705253 dose-dependently and significantly attenuated cholinergic neurodegeneration. Calpain inhibition also significantly diminished the accompanying gliosis, as determined by immunohistochemical analysis of microglia activation. Finally, inhibition of calpain by A-705253 and the peptidic calpain inhibitor ALLN did not impair long-term potentiation in hippocampal slices indicating that calpain inhibition interrupts NMDA excitotoxicity pathways without interfering with NMDA receptor mediated signaling involved in cognition. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of excitotoxicity-induced neuronal decline without interference with physiological neuronal functions associated with learning and memory processes. Calpain inhibition thus may be a promising and novel approach for the treatment of various neurodegenerative disorders.

Key words: LTP, NMDA, calpain, cholinergic, neuroprotection, nucleus basalis