A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia.
Although a number of studies have demonstrated the neuroprotective effects of antagonists of postsynaptic N-methyl-D-aspartate (NMDA) and non-NMDA receptors in cerebral ischemia, little is known about the treatment of cerebral infarction through presynaptic blocking of extracellular glutamate release. We evaluated the effects of a presynaptic selective N-type calcium channel antagonist (SNX-111, given intravenously by continuous infusion at 5 mg/kg/h from 20 min prior to occlusion until 2 h postocclusion) on blood flow, extracellular glutamate, and infarct volume in rats with permanent occlusions of the right middle cerebral and right common carotid arteries plus 1-h transient occlusion of the left common carotid artery. There was no significant difference in CBF in the occluded cortex during the experiment between the treated and vehicle groups. SNX-111 significantly reduced total amount of extracellular glutamate during the experiment and the peak value of the glutamate after occlusion from 44.2 +/- 15.8 microM (mean +/- SD) to 21.4 +/- 11.4 microM (p < 0.01). Infusion of SNX-111 also significantly reduced the cortical volume of infarction from 47.2 +/- 5.8 to 19.9 +/- 7.3% (p < 0.0001). These results suggest that SNX-111 has a protective effect against focal ischemia through the inhibition of glutamate release from presynaptic sites, although SNX-111 may also affect the release of other neurotransmitters.
Takizawa
S
S
Department of Neurology, Tokai University School of Medicine, Kanagawa, Japan.
Matsushima
K
K
Fujita
H
H
Nanri
K
K
Ogawa
S
S
Shinohara
Y
Y
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002339:Carotid Arteries; D002536:Cerebral Arteries; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003250:Constriction; D018698:Glutamic Acid / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology*; D007700:Kinetics; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D010455:Peptides; D020960:omega-Conotoxins; D018698:Glutamic Acid; C078452:ziconotide