Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels |
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Authors: | Wu Wen-Ning Wu Peng-Fei Chen Xiang-Long Zhang Zui Gu Jun Yang Yuan-Jian Xiong Qiu-Ju Ni Lan Wang Fang Chen Jian-Guo |
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Institution: | Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. |
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Abstract: | BACKGROUND AND PURPOSESinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen-glucose deprivation-reperfusion (OGD-R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism.EXPERIMENTAL APPROACHMiddle cerebral artery occlusion in rats was used as an animal model of ischaemic stroke in vivo. The mechanisms of the effects of SN were investigated in vitro using whole-cell patch-clamp recording, calcium imaging in PC12 cells and rat cortical neurons subjected to OGD-R.KEY RESULTSPretreatment with SN (10 and 30 mg·kg?1, i.p.) significantly decreased brain infarction and the overactivation of calcium-mediated events in rats subjected to 2 h ischaemia followed by 24 h reperfusion. Extracellular application of SN inhibited the currents mediated by acid-sensing ion channel 1a and L-type voltage-gated calcium channels, in the rat cultured neurons, in a concentration-dependent manner. These inhibitory effects contribute to the neuroprotection of SN against OGD-R and extracellular acidosis-induced cytotoxicity. More importantly, administration of SN (30 mg·kg?1, i.p.) at 1 and 2 h after cerebral ischaemia also decreased brain infarction and improved functional recovery.CONCLUSION AND IMPLICATIONSSN exerts potent protective effects against ischaemic brain injury when administered before ischaemia or even after the injury. The inhibitory effects of SN on acid-sensing ion channel 1a and L-type calcium channels are involved in this neuroprotection. |
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Keywords: | sinomenine acid-sensing ion channels voltage-gated calcium channels middle cerebral artery occlusion |
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