Anticonvulsant effects of DN-1417, a novel TRH analog, were examined in kindling preparations which had been established as an experimental 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. The 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 anticonvulsant effects of DN-1417 on both behavioral seizure and afterdischarge induced by amygdaloid stimulation were examined. Further more, changes in FET were examined at 24 hours after drug administration. Autonomic nervous manifestations including vomiting, evacuating of the bowels, hypersalivation and hyperpnea appeared in 7 out of 11 cats, while stereotyped behavior appeared in only one cat. 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 the acute anticonvulsant effect of DN-1417 lasted for a 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 those of indirect dopamine agonists, i.e. methamphetamine, nomifensine and cocaine. The acute anticonvulsant effects of DN-1417 differed from those of such representative antiepileptics as phenytonin, phenobarbital and carbamazepine, which have dose-related and lasting efficacy on the amygdaloid kindled seizure. An assumption that dopamine may relate to the anticonvulsant effect of DN-1417 was made. 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 a long-lasting, anticonvulsant effect has never been reported in terms of kindling preparations. Further study is indicated for an exploration of the mechanism of the long-lasting effect.
|Number of pages||7|
|Journal||Brain and Nerve|
|Publication status||Published - Sep 23 1983|
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