Interaction of the neurosteroid alphaxalone with conventional antiepileptic drugs in different types of experimental seizures.
A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5-5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED(50) value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.
Borowicz
Kinga K
KK
Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090, Lublin, Poland.
Zadrozniak
Marek
M
Swiader
Mariusz
M
Kowalska
Aneta
A
Kleinrok
Zdzisław
Z
Czuczwar
Stanisław J
SJ
D000628:Aminophylline; D000679:Amygdala / Q000502:physiology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D003292:Convulsants; D004347:Drug Interactions; D004597:Electroshock; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D009069:Movement Disorders / Q000188:drug therapy; D010433:Pentylenetetrazole; D004856:Postural Balance / Q000187:drug effects; D011277:Pregnanediones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D014635:Valproic Acid / Q000097:blood / Q000494:pharmacology
D000777:Anesthetics; D000927:Anticonvulsants; D003292:Convulsants; D011277:Pregnanediones; D000628:Aminophylline; D014635:Valproic Acid; C006477:alphaxalone; D010433:Pentylenetetrazole