A Selective N-Type Ca2+-Channel Blocker Prevents CA1 Injury 24 h following Severe Forebrain Ischemia and Reduces Infarction following Focal Ischemia

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Abstract
SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an ω-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). In the 2-h ischemic group, saline-treated controls sustained 211 ± 51 mm3 ( n = 6) of infarction, and SNX-111 infusion attenuated the infarct size to 126 ± 50 mm3 ( 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 reperfusion. In this group, combined treatment resulted in 141 ± 22 mm3 of infarction ( n = 5; p < 0.05). These data suggest that Ca2+ fluxes through ω-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.