The sodium channel blocker RS100642 reverses down-regulation of the sodium channel alpha-subunit Na(v) 1.1 expression caused by transient ischemic brain injury in rats.
In this study we evaluated the expression of five sodium channel (NaCh) Alpha-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 Na(v) 1.1, Na(v) 1.2, Na(v) 1.3, Na(v) 1.7, Na(v) 1.8 and the housekeeping gene beta-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 Na(v) 1.1 and Na(v) 1.2 genes were significantly down-regulated in the ipsilateral hemisphere of the injured brains. RS100642 treatment significantly reversed the down-regulation of Na(v) 1.1 (but not Na(v) 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 Na(v) 1.1 caused by ischemic brain injury and suggests that RS100642 selectively targets the Na(v) 1.1 Alpha-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 Na(v) 1.1 NaCh Alpha-subunit may play a key role in the neuronal injury/recovery process.
Yao
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Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Ave. Rm. 2W14, Silver Spring, MD 20910-7500, USA.
Williams
A J
AJ
Lu
X-C M
XC
Price
R A
RA
Cunningham
B S
BS
Berti
R
R
Tortella
F C
FC
Dave
J R
JR
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008801:Mexiletine / Q000031:analogs & derivatives / Q000494:pharmacology*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C475846:RS100642; C568250:Scn1a protein, rat; C568253:Scn2A protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine