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Uric Acid Induces Cognitive Dysfunction through Hippocampal Inflammation in Rodents and Humans.
- Source :
-
Journal of Neuroscience . 10/26/2016, Vol. 36 Issue 43, p10990-11005. 16p. - Publication Year :
- 2016
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *URIC acid
*METABOLITES
*URATE oxidase
*ALLANTOIN
*GLIOSIS
*NEURODEGENERATION
Subjects
Details
- Language :
- English
- ISSN :
- 02706474
- Volume :
- 36
- Issue :
- 43
- Database :
- Academic Search Index
- Journal :
- Journal of Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 119194590
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1480-16.2016