TRH analog （DN−1417）の抗けいれん効果：第I報—キンドリングモデルを用いた研究

ANTICONVULSANT EFFECT OF A NOVEL TRH ANALOG (DN-1417) ON AMYGDALOID KINDLED SEIZURE

　抄録　TRH analog （DN−1417）は，最近注目されているneuropeptideのひとつであり，現在，数施設で難治性てんかん患者を対象に，臨床治験が進行中である。DN−1417の抗けいれん効果の評価実験を，11匹の扁桃核キンドリングネコを対象にしておこない，次の結果を得た。1）11匹中10匹に，投薬後5〜20分に短時間持続し，用量依存性を欠く急性抗けいれん効果を認めた。2）11匹中4匹に，長期間持続性（9〜50日以上），反復性のけいれん閾値上昇効果がみられ，これにともなつてキンドリングモデルのall or none法則が崩壊していた。DN−1417の急性抗けいれん効果は，従来臨床的に用いられている抗てんかん薬と異なつており，むしろindirect dopamine agonistのそれと類似していた。また，TRHおよびDN−1417が脳内monoamine代謝に促進的に働き，キンドリングモデルでcatecholamine系が抑制系と考えられている点より，そのメカニズムを考察した。しかし，少数例ではあるが，長期間持続性の効果を認めたことに関しては，これまでにも報告がなく，neuropeptideの特異的な抗てんかん効果であるという可能性を指摘した。

Anticonvulsant effects of DN-1417, a novel TRH analog, were examined in kindling prepara-tions which had been established as an experi-mental model of epilepsy (secondary generalized seizure).

Eleven amygdaloid kindled cats were tested. After intravenous administration of DN-1417, final electroconvulsive threshold (FET) stimulation was given to the amygdala. Dose of DN-1417 (0. 5, 1, 2 or 4 mg/kg) and FET stimulation time (5, 10, 15, 20 or 30 min. after the administration) were flexible in this study. Firstly, changes in autonomic nervous manifestations and general behavior were observed. Secondly, acute anticon-vulsant effects of DN-1417 on both behavioral seizure and afterdischarge induced by amygdaloid stimulation were examined. Further more, changes in FET was examined at 24 hours after the drug administration.

The following results were obtained :

1) Autonomic nervous manifestations including vomiting, evacuating of the bowels, hypersaliva-tion and hyperpnea appeared in 7 out of 11 cats, while stereotyped behavior appeared in only one cat.

2) DN-1417 suppressed the kindled generalized seizure in 10 out of 11 cats. Generalized seizure was either changed into partial seizure or blocked completely. But acute anticonvulsant effect of DN-1417 lasted for very short time (5~20 min.), and effective doses ranged from 1 to 4 mg/kg without dose-related efficacy. These characteristics of anticonvulsant effect are identical to these of indirect dopamine agonist, i. e. methamphetamine, nomifensine and cocaine. The acute anticonvulsant effects of DN-1417 differed from those of such representative antiepileptics as Phenytonin, Phe-nobarbital and Carbamazepine, which have dose-related and lasted efficacy on the amygdaloid kindled seizure. An assumption that dopamine may relate to the anticonvulsant effect of DN-1417 was made.

3) Following the positive anticonvulsant effect, FET was elevated after 24 hours of the drug administration in 4 out of 10 cats. This effect could be reconfirmed and persisted for 9 to 40 days. Such long-lasting anticonvulsant effect has never reported in terms of kindling preparations. Further study is proceeded for an exploration of the mechanism of the long-lasting effect.