title: Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes.
abstract: 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 (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38-mitogen-activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin-treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) 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 rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes.
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelsaid
authors.affiliation: Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA.
authors.forename: Roshini
authors.initials: R
authors.lastname: Prakash
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA.
authors.forename: Maha
authors.initials: M
authors.lastname: Coucha
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA.
authors.forename: Sherif
authors.initials: S
authors.lastname: Hafez
authors.affiliation: Department of Biostatistics, Georgia Regents University, Augusta, GA.
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, GA Department of Physiology, Georgia Regents University, Augusta, GA Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000098:blood supply / Q000502:physiology*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013312:Stress, Physiological; D020521:Stroke / Q000378:metabolism / Q000473:pathology*; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D021122:Protein Subunits; D014443:Tyrosine; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases