Neurotoxic Convulsions Induced by Histamine H2Receptor Antagonists in Mice

Abstract

Convulsive potency was evaluated to investigate the mechanism of neurotoxic convulsion induced by histamine H2receptor antagonists (H2blockers). Four H2blockers, cimetidine (721–1236 nmol), ranitidine (477–954 nmol), famotidine (7.4–44 nmol), and nizatidine (226–603 nmol) were administered intracerebrally (ic) to mice. Dose dependency of clonic and/or tonic convulsion was observed, and the ED50 values of convulsive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pretreatment of muscimol, aminooxy acetic acid, diazepam, (±)2-amino-7-phosphonoheptanoic acid (APH), or (+)MK801 suppressed the tonic convulsion after ic administration of ranitidine, but had no effect on clonic convulsion. Furthermore, the convulsive threshold concentration in the brain determined by constant rate infusion of ranitidine was not affected by the pretreatment of muscimol, diazepam, APH, and MK801. ED50 values for convulsive occurrence after ic administration of four H2blockers correlated well with the EC50 values for gastric acid secretion inhibition. The convulsive threshold concentrations of cimetidine and ranitidine in the brain were 11 and 2.5 μM, respectively, which were similar to the dissociation constants determined from the inhibition of gastric acid output in mice. From these results, tonic convulsion induced by H2blockers can be suppressed by GABAergic or glutamatergic anticonvulsants, while clonic convulsion induced by H2blockers may be associated with the blockade of H2receptor in the brain and not be directly associated with the GABA and glutamate-mediated neurotransmission.