TRH analog （DN−1417）の抗けいれん効果第Ⅲ報，てんかん予防効果について—キンドリングモデルを用いた研究

PROPHYLACTLC EFFECTS OF A NOVEL TRH ANALOG (DN-1417) ON AMYGDALOID KINDLING IN CATS

　抄録　私どもはこれまでの実験で，TRHの新しい誘導体，DN−1417がキンドリングモデルのてんかん様反応に抗けいれん効果をもつてとを報告し，その急性効果に脳内カテコラミン系の機能亢進が深く関しているものと推論した。今回は10匹のネコを用いて，DN−1417のキンドリング発展に対する予防効果を検討した。DN−1417群（N＝4）には各回刺激5分前にDN−14171mg／kgを腹腔内投与し，後発射閾値強度，1日1回，1秒間，60Hzで一側扁桃核を刺激した（drug session）。36回目以後の刺激は1日のwash out期間をおいておこなった。キンドリング完成までの刺激回数，ADおよび発作症状の発展，反対側扁桃核への転移現象について，対照群と比較した。その結果，DN−1417群では1匹を除いてキンドリング完成が遅延し，後発射の分断（fragmentation）と他脳部位への伝播抑制もみられた。また転移現象は2匹で阻止された。このように，DN−1417のキンドリング予防効果は，先に報告した急性抗けいれん効果に比べて一層顕著であった。予防効果の機序として，カテコラミン作動系への薬理作用が密接に関与しているてとを考察した。また今回示された転移現象の阻止は，キンドリングの基盤をなす経シナプス性変化をDN−1417が阻害したことを示唆するものであり，その機序を蛋白合成の側面より考察した。

We reported previously that TRH・T and a novel TRH analog, DN-1417 had anticonvulsant effects in kindling cat preparations which had been established as an experimental model of epilepsy. Although acute anticonvulsant effect of DN-1417 was short-lasting without dose-related efficacy, DN-1417 administration resulted a lasting increase in convulsive threshold in some cases.

In order to study the effects of DN-1417 on kindling seizure development (prophylactic effect), 10 amygdaloid kindling cats were examined. The animals in the DN-1417 group (N=4) were treated with the agent (1mg/kg) prior to each daily kindling stimulation for 35 days (drug sessions). Six cats in control group were kindled without drug treatment. Kindling rates, changes in after-discharge duration, and positivity of transference phenomenon to contralateral amygdala were compared between these two grous. The results obtained were : 1) Positive prophylactic effects on kindling was found in 3 cats of DN-1417 group. In these cats, 19 (7-37) additional daily stimulation to those given during the drug session were required for the kindling. 2) No positive transfer to contralateral amygdala was found in 2 of 3 cats of DN-1417 group. 3) During the drug sessions, self-sustained afterdischarges were fragmented into separated bursts of discharges with short duration in 2 cats of DN-1417 group.

These results suggested that DN-1417 may prevent a trans-synaptic change underlying the kindling, which might relate to the long-lasting anticonvulsant effect reported clinically. A possible mechanism underlying the prophylactic effects of DN-1417 was discussed. It is postulated that central catecholaminergic system may participate to the prophylactic effects of DN-1417 on kindling.