Antiepileptic effects of CNK-602A, a novel thyrotropin-releasing hormone analog, on absence-like and tonic seizures of spontaneously epileptic rats.

The effects of CNK-602A (N-(6-methyl-5-oxo-3-thiomorpholinyl) carbonyl]-L-histidyl-L-prolinamide), a novel thyrotropin-releasing hormone related analog, were investigated on absence-like seizure and tonic convulsion in the spontaneously epileptic rat (SER), which is a genetically defined double-mutant. When CNK-602A of 0.2-1 mg/kg was given intravenously to the animal, there were no changes in the background EEG except for an increase in low-voltage fast waves concomitant with behavioral alertness. However, CNK-602A suppressed absence-like seizure and tonic convulsion in a dose-dependent manner for over 1 h. These antiepileptic effects of CNK-602A on both seizures were antagonized by pretreatment with haloperidol (1 mg/kg, i.p.). It was found, using a brain in vivo microdialysis method, that CNK-602A at a dose of 1 mg/kg, which inhibits the seizures, increased the release of dopamine in the caudate nucleus. These results suggest that CNK-602A inhibits the seizures of SER in a similar manner to thyrotropin-releasing hormone (TRH), probably by increasing the release of dopamine in the central nervous system. In addition, the antiepileptic effects of CNK-602A were more potent and lasted longer than those of TRH.