Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion.
BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5- trichlorophenyl)pyrimidine is a use-dependent blocker of voltage-dependent sodium channels that blocks veratrine-induced glutamate release in vitro. The aim of this study is to determine if BW619C89 inhibits glutamate release and is neuroprotective in cerebral ischemia produced by proximal middle cerebral artery (MCA) occlusion in rats. Infarct volume was determined at 24 hr after permanent MCA occlusion from 2,3,5-triphenyltetrazolim hydrochloride-stained sections. Pretreatment with BW619C89 (10, 20, 30 and 50 mg/kg i.v. of mesylate salt) decreased infarct volume in a dose-dependent fashion maximal at 30 mg/kg compared to saline controls. Treatment with 30 mg/kg up to 45 min after MCA occlusion also was effective. Microdialysate glutamate in rats treated with 30 mg/kg of drug before MCA occlusion was decreased in both caudate (ischemic core) and rostral cortex (penumbra) compared to controls. BW619C89 did not induce significant arterial hypotension, except when it was administered by rapid bolus administration. In this case, the hypotension was transient and did not reduce efficacy or superficial cortical blood flow. BW619C89 did not induce the 72 kD heat shock protein in cingulate gyrus or retrosplenial cortex as did MK801, suggesting that BW619C89 does not injure neurons in these regions as do N-methyl-D-aspartate antagonists. These results suggest that inhibition of glutamate release by BW619C89 may be an effective and nontoxic treatment for stroke.
Graham
S H
SH
Department of Neurology, University of California, San Francisco.
Chen
J
J
Lan
J
J
Leach
M J
MJ
Simon
R P
RP
D000818:Animals; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D015640:Ion Channel Gating; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers
D005971:Glutamates; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D018698:Glutamic Acid; C081980:sipatrigine