Background: Over 40% of patients with liver cirrhosis also suffer from cognitive impairments, mainly from hepatic encephalopathy (HE). This reversible and episodic syndrome leads to gross disorientation, asterixis, memory impairments, and death and is associated with an increase in blood ammonia. However, some patients with cirrhosis present with cognitive alterations in absence of increased ammonia circulation. This justifies investigating other factors that may induce further cerebral lesions than what is seen in HE. With this project, we focus on the role of uric acid (UA) and hyperuricemia in inducing cognitive impairments in cirrhosis. Hyperuricemia is associated with metabolic syndrome and chronic alcohol consumption which are known precipitating factors of CLD. Furthermore, uric acid (UA) has been reported to be involved in the induction of neuroinflammation and cell loss by apoptosis and pyroptosis, leading to anxiety-like behavior and memory impairment. This project uses a joint murine model of chronic liver disease and hyperuricemia to investigate behavioral alterations and cerebral lesions. Method: To induce liver cirrhosis we used the well-characterized model of bile-duct ligation (BDL) knowing that these animals also develop symptoms of ammonia-related HE. Fifty-two male Sprague-Dawley rats (200-240 g) were randomly assigned to a control (SHAM) or a BDL surgery. To induce hyperuricemia, half of the animals were fed a high uric acid diet (HUAD) (3% uric acid), dividing our rats into 4 groups: (1) SHAM+regular diet (RD), (2) SHAM+HUAD, (3) BDL+RD and (4) BDL+HUAD. Plasma UA measurements were made on days 0, 7, 14, 21, and 28. Behavior tests were conducted to measure anxiety (open-field test and elevated plus-maze) and short and long-term memory (novel-object recognition) at days 14 and 28. At day 33, the rats were sacrificed, their brains collected, and the frontal cortex, hippocampus, and amygdala were isolated to assess cell death by measuring caspase-3 (apoptosis) and caspase-1 (pyroptosis) activity. Result(s): HUAD significantly increased circulating UA in BDL rats. This was associated with a significant decrease in short-term memory without changes in anxiety-like behavior for HUAD rats compared to their RD counterparts in both SHAMs and BDLs. For long-term memory, BDLs were shown to be significantly impaired compared to SHAMs. A significantly higher degree of impairment was seen in BDL+HUAD rats compared to BDL+RD. Cell death (apoptosis and pyroptosis) was then evaluated in the limbic system to explain some of the behavioral changes. In the frontal cortex, we can see a significant increase of caspase-3 activity in the SHAM+HUAD animals when compared to the SHAM+RD rats and no changes for caspase-1 activity. In the amygdala, we see a significant increase of caspase-3 activity in the BDL+HUAD rats when compared to all three other groups and a significant increase of caspase-1 in the SHAM+HUAD and BDL+HUAD groups when compared to their RD counterparts. In the hippocampus, we see a significant increase of caspase-3 activity for the SHAM+HUAD and BDL+HUAD groups when compared to their RD counterparts. We also detect a significant increase of caspase-1 activity in both HUAD groups. Conclusion(s): In SHAM rats, diet-induced hyperuricemia shows a significant increase in circulating uric acid concentration as well as short-term memory loss associated with apoptosis (caspase-3 activity) in the frontal cortex and the hippocampus. In BDL rats, hyperuricemia induces long-term memory impairments and apoptosis in the frontal cortex as well as pyroptosis in the hippocampus. The results from this study show the merit of further investigating the role of hyperuricemia in cognitive impairment in the context of liver cirrhosis.
