Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke
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ORIGINAL ARTICLE
Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke Alicia Aliena-Valero 1,2 & Sergio Rius-Pérez 2 & Júlia Baixauli-Martín 2 & Germán Torregrosa 1 & Ángel Chamorro 3,4,5 & Salvador Pérez 2 & Juan B. Salom 1,2 Received: 29 February 2020 / Accepted: 2 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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-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. Keywords Ischemic stroke . Uric acid . Neuroprotection . IL-6/STAT3 pathway . Rat model Alicia Aliena-Valero and Sergio Rius-Pérez contributed equally to this work.
Introduction
* Salvador Pérez [email protected]
Uric acid (UA) is the end product of purine metabolism in humans and a major endogenous antioxidant in blood [1]. Moreover, systemic infusion of high UA doses was safe and increased serum antioxidant capacity in healthy humans [2]. As to acute ischemic stroke, the potential neuroprotective role of UA has been investigated in both preclinical and clinical scenarios. With regard to preclinical studies, mice heterozygous for a disrupted urate oxidase transgene (UOX+/−), with elevated serum UA levels, showed reduced brain damage and improved functional outcome after ischemic stroke [3]. Moreover, several studies hav
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