title: Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans.
abstract: 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.
  
  
  
  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.
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Xiaoni
authors: 0000-0003-3301-5092
authors: X
authors: Shao
authors: Department of Pharmacology, School of Basic Medicine, Anhui Medical University, Hefei 230032, People's Republic of China.
authors: Wenjie
authors: W
authors: Lu
authors: Molecular Imaging Laboratory, Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Fabao
authors: F
authors: Gao
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Dandan
authors: D
authors: Li
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Jing
authors: J
authors: Hu
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Yan
authors: Y
authors: Li
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Zeping
authors: Z
authors: Zuo
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors: Hui
authors: H
authors: Jie
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China, xbcen@scu.edu.cn zhaoyinglan@scu.edu.cn.
authors: Yinglan
authors: Y
authors: Zhao
authors: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China, xbcen@scu.edu.cn zhaoyinglan@scu.edu.cn.|National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China, and.
authors: Xiaobo
authors: X
authors: Cen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004660:Encephalitis / Q000139:chemically induced* / Q000276:immunology*; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014527:Uric Acid / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D014527:Uric Acid
keywords: TLR4/NF-κB signaling pathway; cognitive dysfunction; hippocampal inflammation; hyperuricemia; uric acid