SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice.

Abstract

Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. We evaluated the ability of a novel neuronal calcium channel blocker, SB 201823-A, to block central neuronal calcium influx in vitro and to reduce ischemic injury in two rodent models of focal stroke. Patch-clamp electrophysiology and intracellular Ca2+ imaging in rat hippocampal and cerebellar neurons were used to determine effects on neuronal calcium channel activity. Middle cerebral artery occlusion was performed in Fisher 344 rats and CD-1 mice to determine the effects on rodent focal ischemic injury and neurological deficits. Cardiovascular monitoring in conscious rats was conducted to determine cardiovascular liabilities of the compound. In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36 +/- 8% and 89 +/- 4% after 5 and 20 mumol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5 mumol/L SB 201823-A totally prevented initial calcium influx and reduced later calcium influx by 50 +/- 2.5% after N-methyl-D-aspartate/glycine stimulation (P < .01). KCl depolarization-induced calcium influx also was reduced by more than 95%. In rats, a single treatment with 10 mg/kg IV SB 201823-A beginning 30 minutes after focal ischemia decreased (P < .05) hemispheric infarct by 30.4% and infarct volume by 29.3% and reduced (P < .05) forelimb deficits by 47.8% and hindlimb deficits by 36.3%. In mice, treatments with 10 mg/kg IP SB 201823-A beginning 30 minutes after focal ischemia significantly reduced infarct volume by 41.5% (P < .01). No blood pressure effects were observed with the therapeutic dose of the compound. These results indicate that the new neuronal calcium channel blocker SB 201823-A can block stimulated calcium influx into central neurons and can provide neuroprotection in two models of focal cerebral ischemia without affecting blood pressure. Data from several different studies now indicate that the neuronal calcium channel antagonists are a promising therapy for the postischemic treatment of stroke.