A SELECTIVE N-TYPE CA2+-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 mm(3) of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 +/- 25 mm(3) (n = 9; p < 0.001). In the 2-h ischemic group, saline-treated controls sustained 211 +/- 51 mm(3) (n = 6) of infarction, and SNX-111 infusion attenuated the infarct size to 126 +/- 50 mm(3) (n = 5; p < 0.05). Because of the hypotensive effects of SNX-111, an additional SNX-111-treated group with intravenous norepinephrine blood pressure support was studied, using 2 h of focal ischemia and 22 h of reper fusion. In this group, combined treatment resulted in 141 +/- 22 mm(3) of infarction (n = 5; p < 0.05). These data suggest that Ca2+ fluxes through omega-conopeptide-sensitive N-type Ca2+ channels are critically involved in the pathogenesis of selective neuronal death up to 24 h after ischemia in the hippocampus and that this conopeptide protection extends, even when given late, to neocortical infarct reduction.