Down regulation of sodium channel Na(v)1.1 expression by veratridine and its reversal by a novel sodium channel blocker, RS100642, in primary neuronal cultures.
This study investigated the effects of veratridine-induced neuronal toxicity on sodium channel gene (NaCh) expression in primary forebrain cultures enriched in neurons, and its reversal by a novel sodium channel blocker, RS100642. Using quantitative RT-PCR, our findings demonstrated the expression ratio of NaCh genes in normal fetal rat forebrain neurons to be Na(v)1.2 > Na(v)1.3 > Na(v)1.8 > Na(v)1.1 > Na(v)1.7 (rBII > rBIII > PN3 > rBI > PN1). Veratridine treatment of neuronal cells produced neurotoxicity in a dose-dependent manner (0.25-20 micro M). Neuronal injury caused by a dose of veratridine producing 80% cell death (2.5 micro M) significantly, and exclusively down-regulated the Na(v)1.1 gene. However, treatment of neurons with RS100642 (200 micro M) reversed the down-regulation of the Na(v)1.1 gene expression caused by veratridine. Our findings document for the first time quantitative and relative changes in the expression of various NaCh genes in neurons following injury produced by selective activation of voltage-gated sodium channels, and suggest that the Na(v)1.1 sodium channel gene may play a key role in the neuronal injury/recovery process.
Dave
Jitendra R
JR
Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910-7500, USA. Jit.dave@na.amedd.army.mil
Yao
Changping
C
Moffett
John R
JR
Berti
Rossana
R
Koenig
Michael
M
Tortella
Frank C
FC
D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D008801:Mexiletine / Q000031:analogs & derivatives / Q000494:pharmacology*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D016548:Prosencephalon / Q000196:embryology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014701:Veratridine / Q000008:administration & dosage / Q000494:pharmacology*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C475846:RS100642; C568250:Scn1a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine; D014701:Veratridine