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The sodium channel blocker RS100642 reverses down-regulation of the sodium channel α-subunit Nav 1.1 expression caused by transient ischemic brain injury in rats

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Abstract

In this study we evaluated the expression of five sodium channel (NaCh) α-subunit genes after transient middle cerebral artery occlusion (MCAo) in the rat and the effects of treatment with the NaCh blocker and experimental neuroprotective agent RS100642 as compared to the prototype NaCh blocker mexiletine. The expression of Nav 1.1, Nav 1.2, Nav 1.3, Nav 1.7, Nav 1.8 and the housekeeping gene β-actin were studied in vehicle or drug-treated rats at 6, 24 and 48 h post-MCAo using real-time quantitative RT-PCR. RS100642 (1 mg/kg), mexiletine (10 mg/kg), or vehicle (1 ml/kg) was injected (i.v.) at 30 min, 2, 4, and 6 h post-injury. Following MCAo only the Nav 1.1. and Nav 1.2 genes were significantly down-regulated in the ipsilateral hemisphere of the injured brains. RS100642 treatment significantly reversed the down-regulation of Nav 1.1 (but not Nav 1.2) at 24–48 h post-injury. Mexiletine treatment, on the other hand, had no significant effect on the down-regulation of either gene. These findings demonstrate that treatment with a neuroprotective dose of RS100642 significantly reverses the down-regulation of Nav 1.1 caused by ischemic brain injury and suggests that RS100642 selectively targets the Nav 1.1 α-subunit of the NaCh. Furthermore, our findings strengthen the hypothesis that ischemic injury may produce selective depletion of voltage-gated NaChs, and suggest that the Nav 1.1 NaCh α-subunit may play a key role in the neuronal injury/recovery process.

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Authors and Affiliations

  1. Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Ave. Rm. 2W14, 20910-7500, Silver Spring, MD, USA

    C. Yao, A. J. Williams, X. -C. M. Lu, R. A. Price, B. S. Cunningham, R. Berti, F. C. Tortella & J. R. Dave

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  1. C. Yao
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  2. A. J. Williams
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  3. X. -C. M. Lu
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  4. R. A. Price
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  5. B. S. Cunningham
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  6. R. Berti
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  7. F. C. Tortella
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  8. J. R. Dave
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Correspondence to J. R. Dave.

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Yao, C., Williams, A.J., Lu, X.C.M. et al. The sodium channel blocker RS100642 reverses down-regulation of the sodium channel α-subunit Nav 1.1 expression caused by transient ischemic brain injury in rats. neurotox res 5, 245–253 (2003). https://doi.org/10.1007/BF03033382

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  • DOI: https://doi.org/10.1007/BF03033382

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