P42 Semaglutide Reduces Cognitive Dysfunction in Experimental Non-Alcoholic Steatohepatitis Through Anti-Inflammatory and Neuroprotective Effects
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».