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

Autor: Juan B. Salom, Alicia Aliena-Valero, Ángel Chamorro, Salvador Pérez, Sergio Rius-Pérez, Júlia Baixauli-Martín, Germán Torregrosa
Rok vydání: 2020
Předmět:
0301 basic medicine
Brain Infarction
Male
STAT3 Transcription Factor
Vascular Endothelial Growth Factor A
medicine.medical_treatment
Neuroscience (miscellaneous)
SOD2
Apoptosis
Brain Edema
Pharmacology
medicine.disease_cause
Neuroprotection
Antioxidants
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Edema
medicine
Animals
SOCS3
Rats
Wistar
Neuroinflammation
Ischemic Stroke
Microglia
business.industry
Interleukin-6
Body Weight
Infarction
Middle Cerebral Artery
Uric Acid
030104 developmental biology
medicine.anatomical_structure
Cytokine
Neurology
Gene Expression Regulation
Cytokines
IL-6/STAT3 pathway
Ischemic stroke
Neuroprotection
Rat model
Uric acid
Lipid Peroxidation
medicine.symptom
business
030217 neurology & neurosurgery
Oxidative stress
Signal Transduction
Zdroj: MOLECULAR NEUROBIOLOGY
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
ISSN: 1559-1182
0893-7648
Popis: 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-κB 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-κB 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.
Databáze: OpenAIRE
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