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Ca2+-mediated neuronal death in rat brain neuronal cultures by veratridine: protection by flunarizine

PJ Pauwels, HP Van Assouw, JE Leysen and PA Janssen

Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.

Neuronal cell degeneration was studied in vitro in primary rat brain neuronal cultures grown in serum-free, chemically defined, CDM R12 medium, by measuring lactate dehydrogenase (LDH) released in the culture medium. A Ca2+-dependent neuronal cell degeneration was observed after prolonged and transient exposure 30 microM veratridine. The release of LDH occurred gradually and could be completely prevented by 2 mM ethylene glycol bis (beta-aminoethyl ether)-N,N,N',N'- tetraacetic acid, 0.1 microM tetrodotoxin, and 1 microM flunarizine. Flunarizine was without effect on neuronal cell loss induced by 1 mM glutamate, 1 mM kainic acid, and 5 mM KCN. The lack of effect on neurotoxicity induced by 1 mM glutamate differentiates flunarizine from N-methyl-D-aspartate antagonists such as MK-801. The latter protected at nanomolar concentrations against glutamate-induced neuronal cell death but had a maximal effect only at 0.1 mM on the veratridine- induced released LDH. It is suggested that, besides the excitatory amino acid receptor pathway, prolonged opening of the veratridine- sensitive Na+ channel can be neurotoxic. The latter can be prevented by flunarizine. The role of Na+ channel blockers as therapeutic agents in cerebral ischemia is discussed.

Volume 36, Issue 4, pp. 525-531, 10/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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