Effect of clobenpropit, a centrally acting histamine H3-receptor antagonist, on electroshock- and pentylenetetrazol-induced seizures in mice.
The anticonvulsant activity of clobenpropit, an isothiourea derivative of histamine and potent H3-receptor antagonist, was investigated in two representative seizure models in mice. In the maximal electroshock seizure threshold test, clobenpropit dose-dependently raised the electroconvulsive threshold for tonic (hindlimb extension) seizures, but a significant increase of about 15% was determined only at the high dose of 40 mg/kg i.p. The protective action of this drug was reduced by immepip and (R)-alpha-methylhistamine, selective H3-receptor agonists. In co-medication with two standard antiepileptics, clobenpropit (20 and 40 mg/kg) significantly increased the anticonvulsant effectiveness of carbamazepine and tended to increase the effectiveness of valproate. Additional studies indicated that the high dose of clobenpropit also significantly enhanced the plasma carbamazepine concentration. One the other hand, in the s.c. PTZ seizure threshold test clobenpropit revealed no protective effects. In the rotarod ataxia test, impaired motor function was observed at 80 mg/kg clobenpropit. In conclusion, the present findings indicated no pronounced anticonvulsant effects of clobenpropit against generalized tonic as well as clonic seizures.
Fischer
W
W
Institute of Pharmacology and Toxicology, University of Leipzig, Federal Republic of Germany.
van der Goot
H
H
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002220:Carbamazepine / Q000097:blood / Q000494:pharmacology; D004056:Differential Threshold / Q000187:drug effects; D004597:Electroshock; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology* / Q000523:psychology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D006633:Histamine Antagonists; D007093:Imidazoles; D002220:Carbamazepine; D014635:Valproic Acid; D013890:Thiourea; C086108:clobenpropit; D010433:Pentylenetetrazole