COMPARATIVE-STUDY OF VOLTAGE-SENSITIVE SODIUM-CHANNEL BLOCKERS IN FOCAL ISCHEMIA AND ELECTRIC CONVULSIONS IN RODENTS

This study evaluates the neuroprotective properties of some voltage-se nsitive sodium channel blockers in a model of focal ischaemia. After c urative treatment (0.5 and 24.5 h after insult), well known voltage-se nsitive sodium channel blockers, phenytoin (2 x 100 mg/kg i.p.), carba mazepine (2 x 50 mg/kg i.p.), lamotrigine (2 x 50 mg/kg i.p.) and RP 6 6055 (2 x 8 mg/kg i.p.) were found to protect rats against brain damag e induced by occlusion of the middle cerebral artery, by 40%, 24%, 28% and 44% respectively. These compounds were also active in protecting both mice and rats against tonic convulsions induced by electroshock, Intraperitoneal ED(50) values in mice and rats respectively were of 5. 2 and 12.5 mg/kg for phenytoin, 8.4 and 3.6 mg/kg for carbamazepine, 4 .4 and 3.1 mg/kg for lamotrigine, 3.9 and 0.22 mg/kg for RP 66055. In contrast, lifarizine was totally devoid of activity in these three tes ts. This study extends an accumulation of data in the literature point ing to a therapeutic potential for voltage-dependent sodium channel bl ockers which penetrate the blood brain barrier. Such compounds as phen ytoin, carbamazepine, lamotrigine or RP 66055 may act at sodium channe ls to prevent depolarization, inhibit release of neurotransmitters suc h as glutamate and thus protects the cortex against cellular damage in duced by focal ischaemia by both pre- and post-synaptic inhibition of abnormal neurotransmission.