P42 Semaglutide Reduces Cognitive Dysfunction in Experimental Non-Alcoholic Steatohepatitis Through Anti-Inflammatory and Neuroprotective Effects
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".