TIAGABINE PREVENTS SEIZURES, NEURONAL DAMAGE AND MEMORY IMPAIRMENT INEXPERIMENTAL STATUS EPILEPTICUS

A novel antiepileptic drug, tiagabine ((R)-N-[4,4-di-(3-methylthien-2- yl)but-3-enyl] nipecotic acid hydrochloride), was studied in rats in o rder to determine its efficacy in preventing seizures, seizure-induced neuronal damage and impairment of spatial memory in the perforant pat hway stimulation model of status epilepticus. In pilot experiments, ad ministration of tiagabine (50, 100 or 200 mg/kg/day) with subcutaneous ly implanted Alzet osmotic pumps led to a dose-dependent increase in t iagabine concentrations in the serum and brain. Two days of tiagabine treatment at a dose range of 50-200 mg/kg/day did not change the level s of gamma-aminobutyric acid (GABA), glutamate or aspartate in cistern al cerebrospinal fluid (CSF) compared to the controls. In the pentylen etetrazol test, the maximal anticonvulsive effect of tiagabine adminis tered via osmotic pumps was achieved already with a dose of 50 mg/kg/d ay. In the perforant pathway model of status epilepticus, subchronic t reatment with tiagabine (Alzet pumps, 50 mg/kg/day) completely prevent ed the appearance of generalized clonic seizures during stimulation (P < 0.001). In the same rats, tiagabine treatment reduced the loss of p yramidal cells in the CA3c and CA1 fields of the hippocampus (P < 0.05 ) but not the loss of somatostatin immunoreactive neurons in the hilus . Two weeks after perforant pathway stimulation, the tiagabine-treated rats performed better in the Morris water-maze test than the vehicle- treated rats did (P < 0.001). Our results show that tiagabine treatmen t reduces the severity of seizures in the perforant pathway stimulatio n model of status epilepticus. Possibly associated with the reduction in seizure number and severity, tiagabine treatment also reduced seizu re-induced damage to pyramidal cells in the hippocampus as well as the impairment of the spatial memory associated with hippocampal damage.