DIFFERENTIAL UP-REGULATION OF VOLTAGE-DEPENDENT NA+ CHANNELS INDUCED BY PHENYTOIN IN BRAINS OF GENETICALLY SEIZURE-SUSCEPTIBLE (E1) AND CONTROL (DDY) MICE

We investigated the effect of in vivo administration of an antiepileptic drug, phenytoin, on the saxitoxin binding capacity of receptor site 1 of the Na+ channel alpha-subunit, and the expression activity of the channel messenger RNA in epileptic El mouse brains, as compared with parental ddY mice. Subchronic with phenytoin (25 mg/kg per day) for 14 days increased the [H-3]saxitoxin binding to brain-derived synaptic membranes of both El and control ddY mice in a time dependent manner. This increase plateaued at 21 +/- 4% in El mice and 28 +/- 3% in ddY control mice after administration of phenytoin for seven days. After cessation of treatment with phenytoin [H-3]saxitoxin binding capacity returned to the basal level within two weeks in both ddY and El brains. Scatchard plot analysis revealed that the phenytoin treatment caused a 20-30% increase in maximum binding capacity of [H-3]saxitoxin of both epileptic El and control ddY mice. A single injection of phenytoin (25 mg/kg) elevated the level of Na+ channel messenger RNA within 1 h in ddY mouse brains. The increase in Na+ channel messenger RNA reached a peak (about 80% increase) after 5 h of phenytoin administration in a concentration-dependent manner (6.25-50 mg/kg). On the other hand, in El mouse brains, Na+ channel messenger RNA was not elevated until more than 5 h after phenytoin injection, and was increased by only about 33%. These results indicate that subchronic administration of phenytoin enhanced the expression of voltage-dependent Na+ channel messenger RNA, which was followed by an increase in the number of Na+ channels in both El and ddY mice. However, a single injection of phenytoin revealed a delayed expression of Na+ channel messenger RNA in El mouse brain, compared to ddY brains, suggesting that the molecular basis for up-regulation of Na+ channels in epileptic El brains is abnormal.