Metformin Treatment in Post-stroke Period Prevents Nitrative Stress and Restores Angiogenic Signaling in the Brain in Diabetes.

Metformin Treatment in Post-stroke Period Prevents Nitrative Stress and Restores Angiogenic Signaling in the Brain in Diabetes. Diabetes. 2014 Dec 18; Authors: Abdelsaid M, Prakash R, Li W, Coucha M, Hafez S, Johnson MH, Fagan SC, Ergul A Abstract We have shown that diabetes impedes vascular repair and causes vasoregression in the brain after stroke but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion injury (I/R) inactivates the p85 subunit of PI3K by nitration and diverts the PI3K-Akt-survival signal to the p38MAPkinase-apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration and caspase-3 cleavage were measured in brains from control, diabetic (GK) or GK rats treated with metformin subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVEC) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK BMVECs showed increased basal nitrative stress compared to controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 while decreasing Akt. These effects were associated with impairment of angiogenic response and restored by treatment with the peroxynitrite scav...
Source: Diabetes - Category: Endocrinology Authors: Tags: Diabetes Source Type: research