Down-regulation of sodium channel Nav1.1 expression by veratridine and its reversal by a novel sodium channel blocker, RS100642, in primary neuronal cultures
- 88 Downloads
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 RTPCR, our findings demonstrated the expression ratio of NaCh genes in normal fetal rat forebrain neurons to be Nav1.2>Nav1.3>Nav1.8>Nav1.1>Nav1.7 (rBII>rBIII >PN3>rBI>PN1). Veratridine treatment of neuronal cells produced neurotoxicity in a dose-dependent manner (0.25−20 μM). Neuronal injury caused by a dose of veratridine producing 80% cell death (2.5 μM) significantly, and exclusively down-regulated the Nav1.1 gene. However, treatment of neurons with RS100642 (200 μM) reversed the down-regulation of the Nav1.1. 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 Nav1.1 sodium channel gene may play a key role in the neuronal injury/recovery process.
KeywordsVeratridine Primary neuronal cultures Voltage-gated sodium channels Gene expression Quantitative RT-PCR
Unable to display preview. Download preview PDF.
- Dave JR, Y Lin, HS Ved, ML Koenig, L Chapp, J Hunter and FC Tortella (2001) RS-1000642-198, a novel sodium channel blocker, provides differential neuroprotection against hypoxia/hypoglycemia, veratridine or gluramate-mediated neurotoxicity in primary cultures of rat cerebellar neurons.Neurotoxicity Res. 3, 381–395.CrossRefGoogle Scholar
- Kimura M, K Sawada, T Miyagawa, M Kuwada, K Katayama and Y Nishizawa (1998) Role of glutamate receptors and voltage-dependent calcium and sodium channels in the extracellular glutamate/aspartate accumulation and subsequent neuronal injury induced by oxygen/glucose deprivation in cultured hippocampal neurons.J. Pharm. Exp. Ther. 285, 178–185.Google Scholar
- Novakovic SD, E Tzoumaka, JG McGivern, M Haraguchi, L Sangameswaran, KR Gogas, RM Eglen and JC Hunter (1998) Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions.J. Neurosci. 8, 2174–2187.Google Scholar
- Sangameswaran L, LM Fish, BD Koch, DK Rabert, SG Delgado, M Ilnicke, LB Jakeman, S Novakovic, K Wong, P Sze, E Tzoumaka, GR Stewart, RC Herman, H Chan, RM Eglen and JC Hunter (1997) A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia.J. Biol. Chem. 272, 14805–14809.PubMedCrossRefGoogle Scholar