A SELECTIVE N-TYPE CALCIUM-CHANNEL ANTAGONIST PROTECTS AGAINST NEURONAL LOSS AFTER GLOBAL CEREBRAL-ISCHEMIA

Calcium influx is believed to play a critical role in the cascade of b iochemical events leading to neuronal cell death in a variety of patho logical settings, including cerebral ischemia. The synthetic omega-con otoxin peptide SNX-111, which selectively blocks depolarization-induce d calcium fluxes through neuronal N-type voltage-sensitive calcium cha nnels, protected the pyramidal neurons in the CA1 subfield of the hipp ocampus from damage caused by transient forebrain ischemia in the rat model of four-vessel occlusion. SNX-111 provided neuroprotection when a single bolus injection was administered intravenously up to 24 hr af ter the ischemic insult. These results suggest that the window of oppo rtunity for therapeutic intervention after cerebral ischemia may be mu ch longer than previously thought and point to the potential use of om ega-conopeptides and their derivatives in the prevention or reduction of neuronal damage resulting from ischemic episodes due to cardiac arr est, head trauma, or stroke. Microdialysis studies showed that SNX-111 was 3 orders of magnitude less potent in blocking potassium-induced g lutamate release in the hippocampus than the conopeptide SNX-230, whic h, in contrast to SNX-111, failed to show any efficacy in the four-ves sel occlusion model of ischemia. These results imply that the ability of a conopeptide to block excitatory amino acid release does not corre late with its neuroprotective efficacy.