A selective N-type Ca(2+)-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia.
SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an omega-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia. Adult male Wistar rats were subjected to 10 min of forebrain ischemia followed by 7 days of reperfusion. A single dose of SNX-111 (5 mg/kg) was injected intravenously following delays of either 6 or 24 h after reperfusion. For 11 rats treated with saline, there was 78 +/- 13% CA1 neuronal injury (mean +/- SD); for 11 given SNX-111 delayed by 6 h, injury was reduced to 35 +/- 30% (p < 0.01); and remarkably, treatment delayed by 24 h (n = 10), still resulted in protection, with only 50 +/- 29% injury (p < 0.05). Adult male spontaneously hypertensive rats had transient occlusion of the right middle cerebral artery of 1.5- or 2-h duration followed by 22.5 or 22 h of reperfusion, respectively. Rats were randomly assigned to receive either saline or SNX-111 (5 mg/kg i.v.), with treatment starting immediately after reperfusion (1.5-h ischemic group) or at 1 h following the onset of ischemia (2-h ischemic group). In the 1.5-h ischemic group, saline-treated animals sustained 138 +/- 32 mm3 of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 +/- 25 mm3 (n = 9; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Buchan
A M
AM
University of Ottawa, Ontario, Canada.
Gertler
S Z
SZ
Li
H
H
Xue
D
D
Huang
Z G
ZG
Chaundy
K E
KE
Barnes
K
K
Lesiuk
H J
HJ
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000145:classification / Q000494:pharmacology; D002544:Cerebral Infarction / Q000401:mortality / Q000473:pathology*; D002560:Cerebrovascular Circulation; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009017:Morbidity; D010455:Peptides / Q000494:pharmacology*; D016548:Prosencephalon / Q000098:blood supply*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D016019:Survival Analysis; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide