Uric Acid Protects against Focal Cerebral Ischemia/Reperfusion-Induced Oxidative Stress via Activating Nrf2 and Regulating Neurotrophic Factor Expression.

Bai-Liu Ya,Lin Chen,Li-Li Yuan,Bo Bai,You Wang,Hong-Ju Cheng,Qian Liu,Wen-Yan Liu,Hong-Fang Li,Ting Yu,Wen-Juan Li

doi:10.1155/2018/6069150

Abstract

The aim of this study was to investigate whether uric acid (UA) might exert neuroprotection via activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and regulating neurotrophic factors in the cerebral cortices after transient focal cerebral ischemia/reperfusion (FCI/R) in rats. UA was intravenously injected through the tail vein (16 mg/kg) 30 min after the onset of reperfusion in rats subjected to middle cerebral artery occlusion for 2 h. Neurological deficit score was performed to analyze neurological function at 24 h after reperfusion. Terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling (TUNEL) staining and hematoxylin and eosin (HE) staining were used to detect histological injury of the cerebral cortex. Malondialdehyde (MDA), the carbonyl groups, and 8-hydroxyl-2′-deoxyguanosine (8-OHdG) levels were employed to evaluate oxidative stress. Nrf2 and its downstream antioxidant protein, heme oxygenase- (HO-) 1,were detected by western blot. Nrf2 DNA-binding activity was observed using an ELISA-based measurement. Expressions of BDNF and NGF were analyzed by immunohistochemistry. Our results showed that UA treatment significantly suppressed FCI/R-induced oxidative stress, accompanied by attenuating neuronal damage, which subsequently decreased the infarct volume and neurological deficit. Further, the treatment of UA activated Nrf2 signaling pathway and upregulated BDNF and NGF expression levels. Interestingly, the aforementioned effects of UA were markedly inhibited by administration of brusatol, an inhibitor of Nrf2. Taken together, the antioxidant and neuroprotective effects afforded by UA treatment involved the modulation of Nrf2-mediated oxidative stress and regulation of BDNF and NGF expression levels. Thus, UA treatment could be of interest to prevent FCI/R injury.

Highlights

The principal therapy for cerebral ischemia is the restoration of cerebral blood flow as early as possible
Sections from rats treated with uric acid (UA) had significantly decreased infarct volumes (22.93% ± 3.04%) compared to the vehicle-treated I/R group (40.18% ± 2.30%, P < 0 01)
In this study, where SD rats were exposed to focal cerebral ischemia/reperfusion (FCI/R), we found that UA treatment (16 mg/kg, i.v.) decreased cerebral infarct volume, neurological deficit core, and degree of brain edema, consistent with the previous studies [23,24,25]

Summary

Introduction

The principal therapy for cerebral ischemia is the restoration of cerebral blood flow as early as possible. Recanalization with recombinant tissue plasminogen activator (rt-PA) has been developed to treat acute ischemic stroke. Reperfusion after cerebral ischemia may be injurious and increase the risk of brain hemorrhage, promote the development of cerebral edema, and cause more serious damage to the blood-brain barrier. Acute cerebral ischemia starts with cerebral blood flow interruption that causes severely limited oxygen and glucose supply, eliciting a cascade of pathological events such as excitotoxicity, calcium dysregulation, oxidative stress, and inflammatory that could result in tissue death. Oxidative stress is linked with a progressive increase in reactive oxygen species (ROS), and it affects the pathogenesis of cerebral ischemia/reperfusion (I/R) injury seriously [2,3,4].

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