Inhibition of calpain prevents NMDA-induced cell death and beta-amyloid-induced synaptic dysfunction in hippocampal slice cultures.
OBJECTIVE
Alzheimer's disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid-beta (Abeta). While the Abeta pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Abeta-induced synaptic deficits, as well as NMDA receptor-mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments.


METHODS
Application of the specific, water-soluble calpain inhibitor A-705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Abeta-induced deficits in neurotransmission in CA1, as well as NMDA-induced neuronal cell death.


RESULTS
A-705253 dose-dependently prevented excitotoxicity-induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A-705253 also fully prevented Abeta oligomer-induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model.


CONCLUSIONS
We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.
Nimmrich
V
V
Neuroscience Research, GPRD, Abbott, Ludwigshafen, Germany. volker.nimmrich@abbott.com
Reymann
K G
KG
Strassburger
M
M
Schöder
U H
UH
Gross
G
G
Hahn
A
A
Schoemaker
H
H
Wicke
K
K
Möller
A
A
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission
C500488:A-705253; D016229:Amyloid beta-Peptides; D001549:Benzamides; D016202:N-Methylaspartate; D002154:Calpain