title: Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice.
abstract: Hyperglycemia at stroke onset is associated with poor long-term clinical outcome in numerous studies. Hyperglycemia induces intracellular acidosis, lipid peroxidation, and peroxynitrite production resulting in the generation of oxidative and nitrosative stress in the ischemic tissue. Here, we studied the effects of acute hyperglycemia on in vivo intercellular adhesion molecule-1 (ICAM-1) expression, neutrophil recruitment, and brain damage after ischemia/reperfusion in mice and tested whether the natural antioxidant uric acid was protective. Hyperglycemia was induced by i.p. administration of dextrose 45 min before transient occlusion of the middle cerebral artery. Magnetic resonance imaging (MRI) was performed at 24 h to measure lesion volume. A group of normoglycemic and hyperglycemic mice received an i.v. injection of micron-sized particles of iron oxide (MPIOs), conjugated with either anti-ICAM-1 antibody or control IgG, followed by T2*w MRI. Neutrophil infiltration was studied by immunofluorescence and flow cytometry. A group of hyperglycemic mice received an i.v. infusion of uric acid (16 mg/kg) or the vehicle starting after 45 min of reperfusion. ICAM-1-targeted MPIOs induced significantly larger MRI contrast-enhancing effects in the ischemic brain of hyperglycemic mice, which also showed more infiltrating neutrophils and larger lesions than normoglycemic mice. Uric acid reduced infarct volume in hyperglycemic mice but it did not prevent vascular ICAM-1 upregulation and did not significantly reduce the number of neutrophils in the ischemic brain tissue. In conclusion, hyperglycemia enhances stroke-induced vascular ICAM-1 and neutrophil infiltration and exacerbates the brain lesion. Uric acid reduces the lesion size after ischemia/reperfusion in hyperglycemic mice.
authors.affiliation: Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain. cjmfat@iibb.csic.es.|Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain. cjmfat@iibb.csic.es.
authors.forename: Carles
authors.initials: C
authors.lastname: Justicia
authors.affiliation: Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain.|Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.
authors.forename: Angélica
authors.initials: A
authors.lastname: Salas-Perdomo
authors.affiliation: Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain.|Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-de-Puig
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Lisette H
authors.initials: LH
authors.lastname: Deddens
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Geralda A F
authors.initials: GAF
authors.lastname: van Tilborg
authors.affiliation: Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Castellví
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
authors.affiliation: Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain.|Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Chamorro
authors.affiliation: Departament d'Isquemia Cerebral i Neurodegeneracio, Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de Investigaciones Cientificas (CSIC), Rossello 161, planta 6, 08036, Barcelona, Spain. anna.planas@iibb.csic.es.|Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain. anna.planas@iibb.csic.es.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D015424:Reperfusion / Q000379:methods; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid
keywords: Glucose; ICAM-1 neutrophils; Stroke; Uric acid