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Objective To investigate the role and possible mechanism of action of rhubarb decoction (RD) retention enema in improving inflammatory damage of brain tissue in a rat model of mild hepatic encephalopathy (MHE）. Methods A total of 60 male Sprague-Dawley rats were divided into blank group (CON group with 6 rats) and chronic liver cirrhosis modeling group with 54 rats using the complete randomization method. After 12 weeks，40 rats with successful modeling which were confirmed to meet the requirements for MHE model by the Morris water maze test were randomly divided into model group (MOD group), lactulose group (LT group), low-dose RD group (RD1 group), middle-dose RD group (RD2 group), and high-dose RD group (RD3 group), with 8 rats in each group. The rats in the CON group and the MOD group were given retention enema with 2 mL of normal saline once a day； the rats in the LT group were given retention enema with 2 mL of lactulose at a dose of 22.5% once a day； the rats in the RD1, RD2, and RD3 groups were given retention enema with 2 mL RD at a dose of 2.5，5.0, and 7.5 g/kg, respectively, once a day. After 10 days of treatment, the Morris water maze test was performed to analyze the spatial learning and memory abilities of rats. The rats were analyzed from the following aspects： behavioral status； the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin-1β（IL-1β), interleukin-6（IL-6), and tumor necrosis factor-α（TNF-α) and the level of blood ammonia； pathological changes of liver tissue and brain tissue； the mRNA and protein expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) in brain tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the MOD group, the RD1, RD2, and RD3 groups had a significantly shorter escape latency (all P<0.01), significant reductions in the levels of ALT, AST, IL-1β, IL-6, TNF- α, and blood ammonia (all P<0.05), significant alleviation of the degeneration, necrosis, and inflammation of hepatocytes and brain cells, and significant reductions in the mRNA and protein expression levels of PI3K, AKT, and mTOR in brain tissue (all P<0.05), and the RD3 group had a better treatment outcome than the RD1 and RD2 groups. Conclusion Retention enema with RD can improve cognitive function and inflammatory damage of brain tissue in MHE rats, possibly by regulating the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]