Activation of voltage-dependent sodium channels in cultured cerebellar granule cells induces neurotoxicity that is not mediated by glutamate release

• Published in: Neuroscience 1996-07, Vol.73 (1), p.209-216
• Main Authors: Dargent, B., Arsac, C., Tricaud, N., Couraud, F.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; cerebellar granule cells; Fundamental and applied biological sciences. Psychology; glutamate; Isolated neuron and nerve. Neuroglia; Na + channel; neuronal death; veratridine; Vertebrates: nervous system and sense organs; α-scorpion toxin
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/0306-4522(95)00608-7

Exposure of rat cerebellar granule cell cultures to neurotoxins that specifically enhance the open state probability of voltage-dependent Na+ channels, resulted in neuronal death as estimated by a cell viability assay based on fluorescent staining and 51Cr-uptake. Toxicity was detected within 1 h after addition of 100 μM veratridine and was complete within 10–18 h; it was dose-dependent and was found to be completely abolished by tetrodotoxin, an Na+ channel blocker. When veratridine was replaced by an α-scorpion toxin, similar observations were done. In contrast, when cultured neurons prepared from the cerebral hemisphere of fetal rat brain were exposed to either veratridine or a -scorpion toxin for 18 h or even for a longer time of incubation, no neuronal death was observed. DNA fragmentation analysis showed that the toxicity was not mediated by apoptosis. Neuronal death was neither prevented by glutamate receptor antagonists, nor by depletion of endogenous glutamate, nor by voltage sensitive calcium channel antagonists such as ω-Conotoxin-GVIA (N-type channels), ω-Agatoxin-IVA (P-type channels), nimodipie and nitrendipine (L-type channels). Our study indicates that prolonged opening of Na + channels induced neuronal death of cerebellar granule cells which is not mediated by glutamate and reveals novel neurotoxic mechanism in addition to the well-established excitatory amino acid receptor pathway.