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.

中文翻译：

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尿酸神经保护与大鼠缺血性中风中 IL-6/STAT3 信号通路激活相关。


尽管尿酸（UA）在急性缺血性中风中具有良好的神经保护作用，但其看似多效性的潜在机制尚未完全了解。最近的证据表明转录因子是 UA 的靶标。为了深入了解 UA 的作用机制，我们研究了其对缺血性中风病理生理学最相关特征的相关生物标志物的影响：(1) 氧化应激（抗氧化酶 mRNA 和 MDA），(2) 神经炎症（细胞因子和 Socs3 mRNA， STAT3、NF-κB p65 和反应性小胶质细胞），(3) 脑肿胀（Vegfa、Mmp9 和 Timp1 mRNA），以及 (4) 凋亡细胞死亡（Bcl-2、Bax、caspase-3 和 TUNEL 阳性细胞） ）。成年雄性 Wistar 大鼠接受管腔内细丝短暂大脑中动脉闭塞 (tMCAO)，并在再灌注 20 分钟时静脉注射 UA (16 mg/kg) 或载体（洛克缓冲液）。结果指标是神经功能缺陷、梗塞和水肿。 UA 治疗可减少皮质梗塞和脑水肿以及神经功能损伤。在大脑皮层中，UA增加：（1）减少tMCAO诱导的Vegfa和Mmp9/Timp1比率表达的增加； (2)诱导Sod2和Cat表达并降低MDA水平； (3)诱导Il6表达，上调STAT3和NF-κB p65磷酸化，诱导Socs3表达，抑制小胶质细胞活化； (4) 改善 Bax/Bcl-2 比率并诱导 caspase-3 裂解以及 TUNEL 阳性细胞计数减少。 总之，UA 在缺血性中风中的形态和功能神经保护机制是多方面的，因为它与 IL-6/STAT3 通路的激活、致水肿性 VEGF-A/MMP-9 信号传导的减弱以及相关介质的调节有关。氧化应激、神经炎症和细胞凋亡。