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.
Highlights
Diabetes is a devastating disease of epidemic proportions
Two diabetic rats died during diabetes induction, three nondiabetic and 4 diabetic rats died during ischemia-reperfusion
3) Inhibition of mitoKATP channels blocked the neuroprotective effect of sevoflurane post-conditioning in non-diabetic rats, whereas it had no effect in diabetic rats
Summary
Diabetes is a devastating disease of epidemic proportions. It is estimated that more than 220 million patients are affected by diabetes worldwide [1,2]. Epidemiological studies have suggested that diabetes is a critical risk factor for ischemic stroke, which is one of the leading causes of death and permanent disability in humans [3,4]. Diabetes complicates ischemic injury, leading to increased neuronal damage and poor functional recovery [5,6]. Exploring the mechanisms underlying ischemic brain injury under diabetic conditions and develop more effective therapies for neuroprotection in this population has been a major focus of medical research in recent years. Very few treatments to reduce ischemic brain injury in clinical practice have been established
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