Semaglutide Reduces Cognitive Dysfunction in Experimental Non-Alcoholic Steatohepatitis Through Anti-Inflammatory and Neuroprotective Effects

Background: Cognitive dysfunction is a poorly recognized and debilitating manifestation of non-alcoholic steatohepatitis (NASH). The glucagon-like peptide 1 receptor (GLP-1R) agonist, Semaglutide, is a promising treatment for NASH that has also been shown to improve cognitive function and exhibit neuroprotective effects in neurodegenerative disease models. Given the dual effect of Semaglutide on both liver and brain, it may hold therapeutic potential for NASH-related cognitive dysfunction. We investigated the acute and long-term effects of Semaglutide treatment on cognitive dysfunction and its possible underlying mechanisms in experimental NASH. Methods: NASH was induced using a 16-week high-fat, high-cholesterol (HFHC) diet. Sixty-4 Sprague-Dawley rats were randomized in 4 groups: 1) standard diet, 2) HFHC diet, 3) HFHC diet with Semaglutide treatment (10 weeks), or 4) HFHC diet with acute Semaglutide treatment (10 days). We assessed neurobehaviour, NASH severity, hepatic and systemic inflammation, ammonia and urea synthesis function, and brain synaptic density and microglia activation. Results: NASH animals exhibited impaired non-hippocampal memory in the Fear Conditioning Test and depression-like behaviour during the Forced Swim Test, both of which were prevented by long-term Semaglutide treatment. While biochemical markers of liver injury improved with treatment, histological NASH and liver fat remained unchanged. However, Semaglutide treatment led to a reduction in elevated plasma ammonia and pro-inflammatory cytokines levels observed in NASH animals. In the prefrontal cortex, NASH animals manifest diminished synaptic density, which was ameliorated by Semaglutide, whereas no differences in microglia activation was observed. In animals treated acutely with Semaglutide, cognitive dysfunction persisted, whilst systemic inflammation and liver inflammation remained unchanged. Conclusion: Treatment with Semaglutide for 10 weeks effectively prevented cognitive dysfunction and depression-like behaviour in experimental NASH, whereas acute treatment had no effect. These improvements were attributed to the attenuation of systemic inflammation and protection against loss of synaptic density, rather than the resolution of NASH. Moreover, the treatment ameliorated hyperammonaemia, which may contribute to cognitive dysfunction in NASH. Our findings hold potential implications for the therapeutic management of NASH and its associated cognitive dysfunction, and warrant further confirmation in clinical translational studies (see Figure 1).Figure 1.: Brain autoradiography imaging of synaptic density and microglia activation. Panels A-B show autoradiography images of 3H-UCB-J (A) and 3H-PK11195 (B) total tracer binding concentration (nM) in the prefrontal cortex; 3H-UCB-J is a biomarker for synaptic density, and 3H-PK11195 binds to activated microglia. Synaptic density was diminished in HFHC animals as compared with controls, but restored in HFHC+S animals (C). There was no difference in microglia activation between the groups (D). Group values are shown as bars and reported as mean ± SD for all analyses. *P < 0.05 compared with control group (CT). †P < 0.05 compared with HFHC group.