Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel

Abstract Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BK Ca (K Ca 1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BK Ca channels without changing its single channel amplitude. As BK Ca channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5 mg/kg, 10 mg/kg and 20 mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BK Ca channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BK Ca channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BK Ca channels and merits exploration as a potential therapeutic agent for treating ischemic stroke.