montirelin and Seizures

Spontaneously epileptic rats (SER), which represent a double mutation (zi/zi, tm/tm), spontaneously exhibit both tonic and absence-like seizures. We examine the long-term effects of a thyrotropin-releasing hormone (TRH) analogue, CNK-602A, acute administration of which was effective inhibiting both types of seizures in SER, to determine if this agent could be used to treat epilepsy for long periods. Food pellets containing 0.001% CNK-602A were given ad libitum to SER from age 7 weeks. CNK-602A significantly inhibited tonic convulsions and prolonged survival. There were no alterations in body weight or plasma levels of triiodotHyronine (T3) and thyroxine (T4). These findings indicate that chronic intake of CNK-602A in a dose that does not affect plasma levels of T3 and T4 inhibits tonic convulsions in SER and suggest that this drug may be an effective treatment for convulsive seizures in patients with epilepsy.

Topics: Administration, Oral; Animals; Behavior, Animal; Body Weight; Disease Models, Animal; Eating; Epilepsy; Female; Humans; Male; Rats; Rats, Inbred SHR; Seizures; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

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.

Topics: Animals; Caudate Nucleus; Cerebral Cortex; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Haloperidol; Hippocampus; Male; Rats; Seizures; Thyrotropin-Releasing Hormone