Tiagabine prevents seizures, neuronal damage and memory impairment in experimental 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 order to determine its efficacy in preventing seizures, seizure-induced neuronal damage and impairment of spatial memory in the perforant pathway stimulation model of status epilepticus. In pilot experiments, administration of tiagabine (50, 100 or 200 mg/kg/day) with subcutaneously implanted Alzet osmotic pumps led to a dose-dependent increase in tiagabine 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 levels of gamma-aminobutyric acid (GABA), glutamate or aspartate in cisternal cerebrospinal fluid (CSF) compared to the controls. In the pentylenetetrazol test, the maximal anticonvulsive effect of tiagabine administered via osmotic pumps was achieved already with a dose of 50 mg/kg/day. In the perforant pathway model of status epilepticus, subchronic treatment with tiagabine (Alzet pumps, 50 mg/kg/day) completely prevented the appearance of generalized clonic seizures during stimulation (P < 0.001). In the same rats, tiagabine treatment reduced the loss of pyramidal 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 treatment reduces the severity of seizures in the perforant pathway stimulation model of status epilepticus. Possibly associated with the reduction in seizure number and severity, tiagabine treatment also reduced seizure-induced damage to pyramidal cells in the hippocampus as well as the impairment of the spatial memory associated with hippocampal damage.
Department of Neurology, University of Kuopio, Finland.
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Halonen
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Nissinen
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JA
Jansen
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Pitkänen
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000134:cerebrospinal fluid; D009557:Nipecotic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013004:Somatostatin / Q000378:metabolism; D013226:Status Epilepticus / Q000188:drug therapy* / Q000503:physiopathology; D013702:Temporal Lobe / Q000473:pathology; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D018377:Neurotransmitter Agents; D009557:Nipecotic Acids; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine