Decreased Brain KATP Channel Contributes to Exacerbating Ischemic Brain Injury and the Failure of Neuroprotection by Sevoflurane Post-Conditioning in Diabetic Rats |
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| Authors: | Dongliang Li Bin Huang Jiangdong Liu Liang Li Xingang Li |
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| Institution: | 1. Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China.; 2. Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan City, Shandong Province, China.; 3. Brain Science Research Institute, Shandong University, Jinan City, Shandong Province, China.; 4. Department of Anesthesiology, The people''s hospital of Gaomi, Gaomi City, Shandong Province, China.; Massachusetts General Hospital/Harvard Medical School, United States of America, |
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| Abstract: | Diabetes leads to exacerbating brain injury after ischemic stroke, but the underlying mechanisms and whether therapeutic intervention with anesthetic post-conditioning can induce neuroprotection in this population are not known. We tested the hypothesis that alteration of brain mitochondrial (mito) KATP channels might cause exacerbating brain injury after ischemic stroke and attenuate anesthetic post-conditioning induced neuroprotection in diabetes. We also examined whether hyperglycemic correction with insulin would restore anesthetic post-conditioning in diabetes. Non-diabetic rats and diabetic rats treated with or without insulin were subjected to focal cerebral ischemia for 2 h followed by 24 h of reperfusion. Post-conditioning was performed by exposure to sevoflurane for 15 min, immediately at the onset of reperfusion. The role of the mitoKATP channel was assessed by administration of a selective blocker 5-hydroxydecanoate (5-HD) before sevoflurane post-conditioning or by diazoxide (DZX), a mitoKATP channel opener, given in place of sevoflurane. Compared with non-diabetic rats, diabetic rats had larger infarct volume and worse neurological outcome at 24 h after ischemia. Sevoflurane or DZX reduced the infarct volume and improved neurological outcome in non-diabetic rats but not in diabetic rats, and the protective effects of sevoflurane in non-diabetic rats were inhibited by pretreatment with 5-HD. Molecular studies revealed that expression of Kir6.2, an important mitoKATP channel component, was decreased in the brain of diabetic rats as compared to non-diabetic rats. In contrast, hyperglycemic correction with insulin in diabetic rats normalized expression of brain Kir6.2, reduced ischemic brain damage and restored neuroprotective effects of sevoflurane post-conditioning. Our findings suggest that decreased brain mitoKATP channel contributes to exacerbating ischemic brain injury and the failure of neuroprotection by anesthetic post-conditioning in diabetes. Insulin glycemic control in diabetes may restore the neuroprotective effects of anesthetic post-conditioning by modulation of brain mitoKATP channel. |
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