Yokoyama H, Onodera K, Maeyama K, Sakurai E, Iinuma K, Leurs R, Timmerman H, Watanabe T
Department of Pharmacology I, Tohoku University School of Medicine, Sendai, Japan.
Eur J Pharmacol. 1994 Jul 21;260(1):23-8. doi: 10.1016/0014-2999(94)90005-1.
The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.
研究了新型组胺H3受体拮抗剂氯苯丙哌（VUF-9153）对小鼠电惊厥的影响。氯苯丙哌显著且呈剂量依赖性地缩短了每个惊厥阶段的持续时间。其抗惊厥作用可被组胺H3受体激动剂（R）-α-甲基组胺和依美替丁（VUF-8325）预处理所阻断。这些发现表明，氯苯丙哌对电惊厥的作用是由于脑内内源性组胺释放增加，这与氯苯丙哌剂量依赖性增加脑组氨酸脱羧酶活性的生化结果一致。氯苯丙哌的抗惊厥作用被组胺H1受体拮抗剂美吡拉敏拮抗，但不被组胺H2受体拮抗剂佐兰替丁拮抗，这表明氯苯丙哌抗惊厥作用释放的组胺与突触后神经元的组胺H1受体相互作用。氯苯丙哌对电惊厥作用的当前发现与先前描述的硫代哌酰胺的发现完全一致（Yokoyama等人，1993年，《欧洲药理学杂志》234卷，第129页），支持了中枢组胺能神经元系统参与癫痫发作抑制的假说。
