Protective effect of the antiepileptic drug candidate talampanel against AMPA-induced striatal neurotoxicity in neonatal rats

Abstract

2,3-Benzodiazepines represent a family of specific, noncompetitive AMPA receptor antagonists with anticonvulsant and neuroprotective properties. In this study, the antiexcitotoxic potency of the clinical antiepileptic drug candidate, talampanel (4×2mg/kg), and that of two related 2,3-benzodiazepines, 5-(4-aminophenyl)-8-methyl-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (GYKI 52466) (4×10mg/kg) and GYKI 53784 (4×2mg/kg), was investigated in 7-day-old rats. The AMPA antagonists were applied in four consecutive i.p. injections at 1-h intervals, the first dosage was given shortly after the intrastriatal injection of (S)-α-amino-3-hydroxy-5,7-methylisoxazole-4-propionic acid (AMPA) (2.5nmol). All tested compounds protected animals from brain damage induced by AMPA as assessed 5 days later by using a tissue volume determination method based on computer-aided serial section reconstruction. GYKI 53784 (56.1±5.0% protection) and talampanel (42.5±5.3% protection) were more potent neuroprotective agents than GYKI 52466 (21.8±2.8% protection). Furthermore, the three compounds attenuated the unilateral AMPA injection-induced turning behavior and seizure-like events.Our present findings are in agreement with those of other investigators who found talampanel neuroprotective in various in vivo experimental models. These data indicate that besides being a promising antiepileptic drug candidate talampanel may have a value in the pharmacotherapy of acute and chronic neurodegenerative diseases, including perinatal ischemia/hypoxia-induced brain injuries, as well.