SB 201823-A Antagonizes Calcium Currents in Central Neurons and Reduces the Effects of Focal Ischemia in Rats and Mice

Background and Purpose 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. Methods 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. Results In cultured rat hippocampal cells, calcium current measured at plateau was reduced by 36±8% and 89±4% after 5 and 20 μmol/L SB 201823-A, respectively. In cerebellar granule cells in culture, pretreatment with 2.5...