Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke.

Fecha de publicación: 01/01/2021 Fecha Ahead of Print: 22/09/2020

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

Rius-Perez, Sergio
Baixauli-Martin, Julia
Chamorro, Angel
Perez, Salvador

Grupos

Unidad Mixta de Investigación Cerebrovascular

Leader

Juan Bautista Salom Sanvalero

Abstract

Despite the promising neuroprotective effects of uric acid (UA) in acute ischemic stroke, the seemingly pleiotropic underlying mechanisms are not completely understood. Recent evidence points to transcription factors as UA targets. To gain insight into the UA mechanism of action, we investigated its effects on pertinent biomarkers for the most relevant features of ischemic stroke pathophysiology: (1) oxidative stress (antioxidant enzyme mRNAs and MDA), (2) neuroinflammation (cytokine and Socs3 mRNAs, STAT3, NF-?B p65, and reactive microglia), (3) brain swelling (Vegfa, Mmp9, and Timp1 mRNAs), and (4) apoptotic cell death (Bcl-2, Bax, caspase-3, and TUNEL-positive cells). Adult male Wistar rats underwent intraluminal filament transient middle cerebral artery occlusion (tMCAO) and received UA (16 mg/kg) or vehicle (Locke's buffer) i.v. at 20 min reperfusion. The outcome measures were neurofunctional deficit, infarct, and edema. UA treatment reduced cortical infarct and brain edema, as well as neurofunctional impairment. In brain cortex, increased UA: (1) reduced tMCAO-induced increases in Vegfa and Mmp9/Timp1 ratio expressions; (2) induced Sod2 and Cat expressions and reduced MDA levels; (3) induced Il6 expression, upregulated STAT3 and NF-?B p65 phosphorylation, induced Socs3 expression, and inhibited microglia activation; and (4) ameliorated the Bax/Bcl-2 ratio and induced a reduction in caspase-3 cleavage as well as in TUNEL-positive cell counts. In conclusion, the mechanism for morphological and functional neuroprotection by UA in ischemic stroke is multifaceted, since it is associated to activation of the IL-6/STAT3 pathway, attenuation of edematogenic VEGF-A/MMP-9 signaling, and modulation of relevant mediators of oxidative stress, neuroinflammation, and apoptotic cell death.

Datos de la publicación

ISSN/ISSNe:: 0893-7648, 1559-1182
Tipo:: Article
Páginas:: 408-423
DOI:: 10.1007/s12035-020-02115-w
PubMed:: 32959172
Factor de Impacto:: 1,271 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

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Métricas

Filiaciones

Aliena-Valero, Alicia:: Instituto de Investigación. Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universitat de València, Torre A, Lab 5.05, Ave Fernando Abril Martorell 106, 46026, Valencia, Spain

Departamento de Fisiología, Facultad de Farmacia, Universitat de València, Ave Vicent Andrés Estellés s/n, Burjassot, 46100, Valencia, Spain

Instituto de Investigación. Univ Valencia, Inst Invest Sanitaria La Fe, Unidad Mixta Invest Cerebrovasc, Lab 5-05,Ave Fernando Abril Martorell 106, Valencia 46026, Spain

Univ Valencia, Dept Fisiol, Fac Farm, Ave Vicent Andres Estelles S-N, Valencia 46100, Spain
Rius-Perez, Sergio:: Departamento de Fisiología, Facultad de Farmacia, Universitat de València, Ave Vicent Andrés Estellés s/n, Burjassot, 46100, Valencia, Spain

Univ Valencia, Dept Fisiol, Fac Farm, Ave Vicent Andres Estelles S-N, Valencia 46100, Spain
Baixauli-Martin, Julia:: Departamento de Fisiología, Facultad de Farmacia, Universitat de València, Ave Vicent Andrés Estellés s/n, Burjassot, 46100, Valencia, Spain

Univ Valencia, Dept Fisiol, Fac Farm, Ave Vicent Andres Estelles S-N, Valencia 46100, Spain
Torregrosa, German:: Instituto de Investigación. Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universitat de València, Torre A, Lab 5.05, Ave Fernando Abril Martorell 106, 46026, Valencia, Spain

Instituto de Investigación. Univ Valencia, Inst Invest Sanitaria La Fe, Unidad Mixta Invest Cerebrovasc, Lab 5-05,Ave Fernando Abril Martorell 106, Valencia 46026, Spain
Chamorro, Angel:: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Departamento de Medicina, Universitat de Barcelona, Barcelona, Spain

Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain

Inst Invest Biomed August Pi & Sunyer IDIBAPS, Comprehens Stroke Ctr, Dept Neurosci, Hosp Clin, Barcelona, Spain

Univ Barcelona, Dept Med, Barcelona, Spain
Perez, Salvador:: Departamento de Fisiología, Facultad de Farmacia, Universitat de València, Ave Vicent Andrés Estellés s/n, Burjassot, 46100, Valencia, Spain.

Univ Valencia, Dept Fisiol, Fac Farm, Ave Vicent Andres Estelles S-N, Valencia 46100, Spain
Salom, Juan B.:: Instituto de Investigación. Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universitat de València, Torre A, Lab 5.05, Ave Fernando Abril Martorell 106, 46026, Valencia, Spain.

Instituto de Investigación. Univ Valencia, Inst Invest Sanitaria La Fe, Unidad Mixta Invest Cerebrovasc, Lab 5-05,Ave Fernando Abril Martorell 106, Valencia 46026, Spain

Univ Valencia, Dept Fisiol, Fac Farm, Ave Vicent Andres Estelles S-N, Valencia 46100, Spain

Keywords

IL-6/STAT3 pathway, Ischemic stroke, Neuroprotection, Rat model, Uric acid

Proyectos y Estudios Clínicos

RED DE INVESTIGACION (RENEVAS)

Investigador Principal: ENRIQUE ALBORCH DOMÍNGUEZ

RD06/0026/0006 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN INSTITUTO DE INVESTIGACIÓN SANITARIA DE SANTIAGO DE COMPOSTELA (FIDIS); FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006