Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel

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 BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CP...

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Bibliographic Details
Published in:European journal of pharmacology 2014-07, Vol.735, p.38-43
Main Authors: Li, Hua-Juan, Zhang, Yu-Jiao, Zhou, Li, Han, Feng, Wang, Ming-Yan, Xue, Mao-Qiang, Qi, Zhi
Format: Article
Language:English
Subjects:
Animals
BKCa channels (KCa1.1)
Brain - drug effects
Brain - physiology
Brain ischemia
Chlorpromazine
Chlorpromazine - pharmacology
Chlorpromazine - therapeutic use
In Vitro Techniques
Infarction, Middle Cerebral Artery - drug therapy
Infarction, Middle Cerebral Artery - physiopathology
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - antagonists & inhibitors
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - physiology
Male
Middle cerebral artery occlusion
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Rats, Sprague-Dawley
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Summary: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 BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa 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 (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2014.04.017