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Stroke, Vol 23, 1319-1323, Copyright © 1992 by American Heart Association

ARTICLES

Neuroprotective mechanism of (+)SKF 10,047 in vitro and in gerbil global brain ischemia

PG Lysko, TL Yue, JL Gu and G Feuerstein
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. 19406-0939.

BACKGROUND AND PURPOSE: The N-methyl-D-aspartate receptor is believed to mediate part of the ischemic neuronal damage caused by the excitatory amino acid glutamate. (+)SKF 10,047, the prototypic sigma- agonist, interacts with the N-methyl-D-aspartate receptor. Therefore, we studied the neuroprotective effect of (+)SKF 10,047 on cultured rat cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: Mechanisms of neuroprotection were studied in vitro by measuring calcium influx into cultured rat cerebellar granule cells loaded with fura 2-AM. In vivo neuroprotection of gerbil CA1 hippocampal neurons was studied in a posttreatment regimen following 5 minutes of bilateral carotid artery occlusion and 7 days of reperfusion. RESULTS: In primary cultured rat cerebellar granule cell neurons, (+)SKF 10,047 in a dose-dependent manner diminished intracellular calcium levels of N-methyl-D-aspartate-stimulated neurons by a maximum of 87% (n = 8), with a 50% inhibitory concentration of 0.8 microM. (+)SKF 10,047 did not prevent subsequent calcium influx stimulated by kainic acid or KCl, nor did it interfere with modulation of the kainate response by quisqualic acid. Neuroprotection of 64% (p = 0.006, n = 15) of gerbil CA1 hippocampal neurons was achieved by posttreatment injection followed by minipump infusion. CONCLUSIONS: Neuroprotection by (+)SKF 10,047 most likely involves interaction at the N-methyl-D-aspartate receptor. These results suggest that the benzomorphan class of sigma-agonists may provide neuroprotection in cerebral ischemia and stroke.

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