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) K(
ATP) 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
mitoK(ATP) channel was assessed by administration of a selective blocker
5-hydroxydecanoate (5-HD) before
sevoflurane post-conditioning or by
diazoxide (DZX), a
mitoK(ATP) 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
mitoK(ATP) 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
mitoK(ATP) 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
mitoK(ATP) channel.