Abstracts

RATIONALE: Nefiracetam is a pyrrolidone derivative and have a similar chemical structure of both piracetam and levetiracetam. Piracetam has been used in some countries to treat mental disorders, and was indicated as add-on treatment for myoclonic seizures. Levetiracetam is a novel antiepileptic drug that showed effectiveness in patients with complex partial seizures. At first, Nefiracetam was developed as a novel cognition-enhancing agent. It has reported that this drug improved learning and memory functions in some experimental amnesia models. However, considering its chemical structure, it seemed possible that nefiracetam had a potential antiepileptic effect like piracetam and levetiracetam. In fact, nefiracetam inhibited maximal electroshock seizures in rats. The aim of this study is to evaluate antiepileptic effect of nefiracetam on kainic acid (KA)-induced seizures.
METHODS: KA was focally infused into the left basolateral amygdaloid nucleus, and focal limbic seizures were induced in 43 male Wistar rats. During the seizure status, 10, 50, 100 or 200 mg/kg of nefiracetam or physiological saline (for the control) was intravenously injected. In 25 animals, EEG and behavioral changes were recorded by a vide-EEG system and compared to the control. Seven days later, the animals were sacrificed and the brains were examined histopathologically. In 18 animals, 60 minutes after the drug injection, 14C-2-deoxy-D-glucose was injected intravenously. The animals were decapitated to remove their brains, which were frozen and serially sliced to coronal sections. The sections were exposed on X-ray film to make autoradiograms. Local glucose metabolism was quantitatively analyzed and statistically compared with the control.
RESULTS: Nefiracetam inhibited KA-induced limbic seizures at doses over 100 mg/kg, while the animals sedated immediately after the drug administration. Spike activity was also suppressed on EEG. The sedative effect lasted for 30 to 60 minutes, then the clinical seizure returned. The antiepileptic effect of high-dose nefiracetam was transient, and later, there was no abnormal behavior in the all animals. The lower doses of the drug could not affect KA-induced seizures and had no sedative effect. From the autoradiographic analysis, the propagation of seizure-related hypermetabolic areas was suppressed dose-dependently in nefiracetam-treated groups. Histopathologic findings revealed that nefiracetam inhibited neuronal cell loss in the hippocampus.
CONCLUSIONS: From the results, it was indicated that nefiracetam has an antiepileptic effect and that its application may suppress seizure propagation. Further study is required whether this agent is available as a novel antiepileptic drug.
Support: This research was partially supported by a grant from Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.