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Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice

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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.

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Acknowledgements

We thank Ms. Alba Hernández for the excellent technical assistance. We are indebted to the image platform of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for technical support.

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Authors and Affiliations

  1. 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

    Carles Justicia, Angélica Salas-Perdomo, Isabel Pérez-de-Puig, Clara Castellví & Anna M. Planas

  2. Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Rossello 161, planta 6, 08036, Barcelona, Spain

    Carles Justicia, Angélica Salas-Perdomo, Isabel Pérez-de-Puig, Ángel Chamorro & Anna M. Planas

  3. Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht, Utrecht, the Netherlands

    Lisette H. Deddens, Geralda A.F. van Tilborg & Rick M. Dijkhuizen

  4. Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain

    Ángel Chamorro

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  1. Carles Justicia
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  2. Angélica Salas-Perdomo
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  3. Isabel Pérez-de-Puig
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  6. Clara Castellví
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  7. Rick M. Dijkhuizen
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  8. Ángel Chamorro
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  9. Anna M. Planas
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Correspondence to Carles Justicia or Anna M. Planas.

Ethics declarations

Animal work was conducted with approval of the ethical committee of the University of Barcelona (CEEA) and in accordance with the EU Directive 2010/63/EU and the Spanish and autonomous Catalan laws (Real Decreto 53/2013 and Decreto 214/1997).

Conflict of Interest

Dr. Chamorro is inventor of the patent, “Pharmaceutical composition for neuroprotective treatment in patients with ictus comprising citicoline and uric acid” (no. 20120108532). The other authors report no conflicts.

Funding Information

This work was supported by the Spanish Ministerio de Economia y Competitividad (SAF2014-56279R and DPI2015-64358-C2-2-R) and the Netherlands Organization for Scientific Research (NWO; VIDI 917.76.347).

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Justicia, C., Salas-Perdomo, A., Pérez-de-Puig, I. et al. Uric Acid Is Protective After Cerebral Ischemia/Reperfusion in Hyperglycemic Mice. Transl. Stroke Res. 8, 294–305 (2017). https://doi.org/10.1007/s12975-016-0515-1

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  • DOI: https://doi.org/10.1007/s12975-016-0515-1

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