Effects of hyperglycemia on cerebrovascular structure, function and ischemic brain injury
Elgebaly, Mostafa Mahmoud
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Statement: Admission hyperglycemia impacts ischemic stroke deleteriously but the relative role of acute hyperglycemia (HG) versus diabetes in the pathogenesis of this poor outcome is not clear. We have shown that middle cerebral artery occlusion (MCAO) causes greater hemorrhagic transformation (HT) in diabetic Goto-Kakizaki (GK) rats, a model with increased cerebrovascular matrix metalloprotease (MMP) activity and tortuosity. Objectives: 1) Determining the effect of HG on neurovascular outcomes of stroke in control versus diabetes, 2) Determining whether diabetes-induced cerebrovascular remodeling is MMP-dependant and 3) To show that prevention of vascular remodeling by glycemic control or MMP inhibition reduces HT in diabetic stroke. Methods: HG was achieved by glucose infusion before MCAO in control Wistar and mildly diabetic GK rats. Following 3 h MCAO/21 h reperfusion, we measured infarct size, HT frequency, excess hemoglobin, neurobehavioral outcome and baseline plasma and MCA MMP activity. Following chronic treatment with metformin or minocycline in a different cohort, we measured baseline cerebrovascular remodeling indices, MCA MMP activity and infarct size and HT after MCAO. Results: Infarct size was significantly smaller in diabetes. HG increased neuronal damage in diabetes but not in control. HT frequency and hemoglobin were significantly higher in diabetes. HG augmented HT in control but not in diabetes. Baseline plasma MMP-9 activity was significantly higher in diabetes. HG increased MMP-9 activity in control and diabetes. Neurological deficit was greater in diabetes. All remodeling markers including MMP-9 activity were increased in diabetes and both metformin and minocycline prevented these changes. Infarct size was smaller in minocycline-treated animals and both metformin and minocycline reduced incidence and severity of HT. Conclusions: HG worsens outcome from ischemic stroke and induces HT in control rats. A further glycemic increase in diabetes does not worsen HT suggesting baseline vascular damage. Higher basal plasma MMP-9 levels in diabetes are associated with higher HT. Since 24 h levels do not correlate with HT, earlier time points merit investigation. Diabetes-mediated stimulation of cerebrovascular MMP-9 activity promotes cerebrovascular remodeling and greater HT in diabetes. Metformin and minocycline offer vascular protection for diabetes patients who are at a 4 to 6-fold higher risk for stroke.