PNU-151774E PROTECTS AGAINST KAINATE-INDUCED STATUS EPILEPTICUS AND HIPPOCAMPAL-LESIONS IN THE RAT

Kainic acid-induced multifocal status epilepticus in the rat is a mode l of medically intractable complex partial seizures and neurotoxicity. The exact mechanisms of kainic acid epileptogenic and neurotoxic effe cts are unknown, but enhanced glutamate release seems to be an importa nt factor. PNU-151774E ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate) is a broad-spectrum new anticonvulsant with Naf channel-blocking and glutamate release inhibiting properties. We have examined the effect of pretreatment with this compound on bot h seizure activity and hippocampal neuronal damage induced by systemic injection of kainic acid in rats. Lamotrigine, a recently developed a nticonvulsant with similar glutamate release inhibitory properties, wa s tested for comparison, together with diazepam as reference standard, on the basis of its anticonvulsant and neuroprotectant properties in this animal model. PNU-151774E, lamotrigine (10, 30 mg/kg;i.p.) and di azepam (20 mg/kg; i.p.) were administered 15 min before kainic acid (1 0 mg/kg; i.p.). In the vehicle-treated group, kainic acid injection ca used status epilepticus in 86% of animals. Hippocampal neuronal cell l oss was 66% in the CA4 hippocampal area at 7 days after kainic acid ad ministration. Diazepam inhibited both seizures and neurotoxicity. Lamo trigine reduced hippocampal neuronal cell loss at both doses, even whe n it did not protect from seizures, although it showed a trend toward protection. On the other hand PNU-151774E protected from both hippocam pal neurodegeneration and status epilepticus. Thus, these data support the concept that seizure prevention and neuroprotection might not be tightly coupled. Glutamate release inhibition may play a major role in neuroprotection, but an additional mechanism(s) of action might be re levant for the anticonvulsant activity of PNU-151774E in this model. ( C) 1998 Elsevier Science B.V. All rights reserved.