Attenuation of AMPA-induced neurotoxicity by a calpain inhibitor.
The effects of a membrane-permeable inhibitor of calpain, Cbz-Val-Phe-H, were examined in an in vitro model of neurotoxicity. Cerebellar slices from young rats were treated with the glutamate receptor agonist, amino-3-hydroxy-5-methyl-4-isoazole propionic acid (AMPA), and cytotoxicity was quantified using conventional histological techniques. Slices treated with AMPA exhibited damage to 83.0% of cerebellar Purkinje cells. In contrast, only 23.6% of Purkinje cells were damaged in slices treated with Cbz-Val-Phe-H and AMPA. These findings indicate that calcium-activated proteolysis is a critical event in AMPA-induced toxicity, and provide evidence that calpain inhibitors are capable of attenuating this form of excitotoxic damage in the central nervous system.
Caner
H
H
Department of Neurological Surgery, University of Virginia, Charlottesville 22908.
Collins
J L
JL
Harris
S M
SM
Kassell
N F
NF
Lee
K S
KS
D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D002531:Cerebellum / Q000473:pathology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D004151:Dipeptides; D007051:Ibotenic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002154:Calpain; C058076:calpain inhibitor III