title: L-2-chloropropionic acid-induced cerebellar granule cell necrosis is potentiated by L-type calcium channel antagonists.
abstract: We have used the model of L-2-chloropropionic acid (L-CPA)-induced selective cerebellar granule necrosis to study excitatory amino acid-induced necrotic cell death in vivo produced by the activation of N-methyl-D-aspartate (NMDA) receptors. However, the mechanism for the NMDA receptor activation and the biochemical events which dictate the anatomical selectivity for the L-CPA-induced lesion are as yet unknown. We examined whether blockade of sodium and calcium channels may reduce the neurotoxicity through a reduction of glutamate release from granule cells. None of the sodium channel antagonists examined, i.e. phenytoin, lamotrigine or rilazole nor the mixed sodium/calcium channel blocker, lifarazine, altered the L-CPA neurotoxicity. However, L-type calcium channel blockers, verapamil and nifedipine enhanced the L-CPA-induced granule cell necrosis, assessed by measuring the degree of L-CPA-induced reductions in cerebellar aspartate concentration, increases in cerebellar glycine concentrations and the development of cerebellar oedema. In addition, the locomotor activity of rats receiving both L-CPA and either verapamil or nifedipine was significantly lower than when rats received L-CPA alone, suggesting an enhancement of the neurotoxicity of L-CPA by L-type calcium channel blockade. The data suggest that L-CPA may interfere with non-L-type calcium channels located on granule cell bodies and nerve terminals leading to reduction of the calcium entry into the cells. We suggest that a combination of L-type channel blockade and non-L-type channels which are sensitive to L-CPA produces reductions in intracellular calcium concentrations below that required for neuronal survival.
authors.affiliation: ZENECA Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
authors.forename: P S
authors.initials: PS
authors.lastname: Widdowson
authors.forename: A
authors.initials: A
authors.lastname: Gyte
authors.forename: R
authors.initials: R
authors.lastname: Upton
authors.forename: J C
authors.initials: JC
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Pitts
authors.forename: R
authors.initials: R
authors.lastname: Moores
authors.forename: I
authors.initials: I
authors.lastname: Wyatt
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002526:Cerebellar Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005998:Glycine / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009336:Necrosis; D009543:Nifedipine / Q000633:toxicity; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014700:Verapamil / Q000633:toxicity
chemical_list: D002121:Calcium Channel Blockers; D006843:Hydrocarbons, Chlorinated; D011422:Propionates; D001224:Aspartic Acid; D012964:Sodium; C021974:2-chloropropionic acid; D014700:Verapamil; D009543:Nifedipine; D005998:Glycine