Inhibitory effects of calcium channel antagonists on motor dysfunction induced by intracerebroventricular administration of paraquat.
This study reports the effects of Ca2+ channel blockers (Ca antagonists) on intraneuronal Ca2+ ([Ca2+]i) movements and on the disturbance of rotarod performance produced in rats by intracerebroventricular administration of paraquat. Paraquat (50 nmol) produced a decrement in rotarod performance which was present at 30 min. and maximal at 60 min. and was not associated with overt behavioural changes; larger doses of paraquat (100-400 nmol intracerebroventricularly) produced paresis and convulsions which severely disrupted rotarod behaviour. The disruption of rotarod performance after paraquat (50 nmol intracerebroventricularly) was significantly reduced by giving Ca antagonists (flunarizine, verapamil and nicardipine) not only intraperitoneally 15 min. after paraquat but also intracerebroventricularly immediately before paraquat. The order of pharmacological potency was flunarizine > or = verapamil > nicardipine. In contrast, intracerebroventricular administration of Bay K 8644, a Ca agonist, enhanced the disruption of rotarod performance caused by paraquat (50 nmol). In in vitro studies, paraquat markedly potentiated the rapid increase in [Ca2+]i levels evoked by 50 mM KCl in rat brain synaptosomal fraction, although paraquat alone produced a small prolonged rise in [Ca2+]i levels which had a slow onset. The above results suggest that paraquat induced neurotoxicity is associated with increased [Ca2+]i levels in brain neuronal cells, and that paraquat might effect on membrane activity instability.
Yoshimura
Y
Y
Department of Pharmacology, Tokyo Medical College, Japan.
Watanabe
Y
Y
Shibuya
T
T
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016257:Fura-2 / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010269:Paraquat / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects
D002121:Calcium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D010269:Paraquat; D002118:Calcium; D016257:Fura-2