Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans
Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans
复制标题
尿酸通过啮齿动物和人类海马炎症诱发认知功能障碍
DOI：
10.1523/jneurosci.1480-16.2016
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发表时间：
2016-10-26
影响因子：
5.3
通讯作者：
Cen, Xiaobo
中科院分区：
文献类型：
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作者：
Shao, Xiaoni;Lu, Wenjie;Cen, Xiaobo
尿酸（UA）是一种嘌呤代谢产物，在大多数哺乳动物中，它会被肝脏中的尿酸酶降解为尿囊素。流行病学研究表明，尿酸水平升高预示着认知和记忆功能障碍的发生；然而，目前尚无这一关系的直接证据，其潜在机制也基本未明确。在此，我们发现高尿酸饮食会触发促炎细胞因子的表达，激活Toll样受体4（TLR4）/核因子（NF）-κB通路，并加剧Wistar大鼠海马体中的神经胶质增生。随后，我们确定了一种NF-κB的特异性抑制剂BAY11 - 7085，并发现对C57BL / 6小鼠进行立体定向注射该抑制剂，能显著改善尿酸诱导的海马体炎症和记忆障碍。我们还发现，在给予尿酸后，原代培养的海马体细胞中的NF-κB被激活。此外，缺乏TLR4的C57BL / 6小鼠能在很大程度上免受尿酸诱导的认知功能障碍的影响，这可能是由于海马体中炎症基因表达的减少。重要的是，磁共振成像证实，大鼠和人类的高尿酸血症与海马体中的神经胶质增生有关。综上所述，这些结果表明，尿酸可通过TLR4 / NF-κB通路引发海马体炎症，进而导致认知功能障碍。我们的研究结果为对抗尿酸诱导的神经退行性变提供了一种潜在的治疗策略。
Uric acid (UA) is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. Epidemiological studies have shown that an elevated UA level predicts the development of cognition and memory deficits; however, there is no direct evidence of this relationship, and the underlying mechanism is largely undefined. Here, we show that a high-UA diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. We, subsequently, identify a specific inhibitor of NF-κB, BAY11-7085, and show that stereotactic injections of the inhibitor markedly ameliorate UA-induced hippocampal inflammation and memory deficits in C57BL/6 mice. We also found that NF-κB is activated in the primary cultured hippocampal cells after UA administration. Additionally, C57BL/6 mice that lack TLR4 are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Importantly, magnetic resonance imaging confirms that hyperuricemia in rats and humans is associated with gliosis in the hippocampus. Together, these results suggest that UA can cause hippocampal inflammation via the TLR4/NF-κB pathway, resulting in cognitive dysfunction. Our findings provide a potential therapeutic strategy for counteracting UA-induced neurodegeneration. SIGNIFICANCE STATEMENT This work demonstrates that a high-uric acid (UA) diet triggers the expression of proinflammatory cytokines, activates the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increases gliosis in the hippocampus of Wistar rats. Inhibition of the NF-κB signaling pathway markedly ameliorates UA-induced hippocampal inflammation and cognitive dysfunction in C57BL/6 mice. TLR4-knock-out mice are substantially protected against UA-induced cognitive dysfunction, possibly due to a decrease in inflammatory gene expression in the hippocampus. Moreover, magnetic resonance imaging confirms that hyperuricemia in rats and humans are associated with gliosis in the hippocampus. Together, this study suggests that there is an important link between UA-induced cognitive dysfunction and hippocampal inflammation in rodents and humans, which may have remarkable implications in the treatment of UA-induced neurodegeneration.