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 treatment with phenytoin (25 mg/kg per day) for 14 days increased the [3H]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, [3H]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 [3H]saxitoxin binding without any change in equilibrium dissociation constant in the brain cortical synaptic membranes 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%.(ABSTRACT TRUNCATED AT 250 WORDS)
Sashihara
S
S
Department of Neurology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Yanagihara
N
N
Izumi
F
F
Murai
Y
Y
Mita
T
T
D029845:Amphibian Proteins; D000818:Animals; D002352:Carrier Proteins; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D010672:Phenytoin / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012530:Saxitoxin / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D013574:Synaptosomes / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D014701:Veratridine / Q000494:pharmacology
D029845:Amphibian Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D015222:Sodium Channels; C027525:saxitoxin-binding protein, Rana catesbeiana; D012530:Saxitoxin; D013779:Tetrodotoxin; D010672:Phenytoin; D014701:Veratridine