Inhibition of Calpain Prevents N-Methyl-D-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction.
N-Methyl-D-aspartate (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 cysteine protease, has been identified as part of such an NMDA receptor-induced excitotoxic signaling pathway. The present study addressed the question of 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, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethlyaminomethylphenyl) ethen-1-yl]benzamide (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 N-acetyl-Leu-Leu-Nle-CHO 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 interfering with the physiological neuronal functions associated with learning and memory processes. Thus, calpain inhibition may be a promising and novel approach for the treatment of various neurodegenerative disorders.
Nimmrich
Volker
V
Neuroscience Research, GPRD, Abbott, Knollstrasse, d-67061 Ludwigshafen, Germany. volker.nimmrich@abbott.com
Szabo
Robert
R
Nyakas
Csaba
C
Granic
Ivica
I
Reymann
Klaus G
KG
Schröder
Ulrich H
UH
Gross
Gerhard
G
Schoemaker
Hans
H
Wicke
Karsten
K
Möller
Achim
A
Luiten
Paul
P
D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects* / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity*; D009410:Nerve Degeneration / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
C500488:A-705253; D001549:Benzamides; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D002154:Calpain