Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia.
The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
C
C
Harada
T
T
Hirai
Y
Y
Fujii
S
S
Harusawa
T
T
Kurihara
C
C
Kamei
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004597:Electroshock / Q000009:adverse effects / Q000379:methods; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017442:Histamine Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006633:Histamine Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007093:Imidazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D007276:Injections, Intraventricular / Q000379:methods; D007550:Isothiuronium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D020547:Lateral Ventricles; D008297:Male; D008761:Methylhistamines / Q000008:administration & dosage / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000008:administration & dosage* / Q000187:drug effects / Q000627:therapeutic use; D012640:Seizures / Q000209:etiology; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D010880:Piperidines; D018100:Receptors, Histamine H3; D007550:Isothiuronium; C077791:iodophenpropit; C069357:alpha-methylhistamine; D013890:Thiourea; C052075:thioperamide; C086108:clobenpropit