Based on the neuroprotective and anti-inflammatory properties of semaglutide, this study aims to investigate whether semaglutide improves core symptoms in BTBR T (+) Itpr3 (tf)/J (BTBR) mice, a model of autism spectrum disorder (ASD), through modulation of inflammation-related targets and signaling pathways.

A total of 32 male C57 BL/6J (C57) and BTBR mice (7 weeks old) were randomly divided into 4 groups (n=8): The treatment group received intraperitoneal injection of 25 nmol/kg semaglutide, while the control group received normal saline, with continuous intervention for 7 d, and body weight was monitored continuously throughout the intervention period. Mouse behavioral indicators were evaluated using various behavioral tests, including the three-chamber sociability test, grooming test, marble-burying test, novel object recognition test, Y-maze test and open field test. After behavioral assessments, the brain tissues were collected, and network pharmacology, GO/KEGG enrichment analysis, protein-protein interaction analysis, molecular docking technology, and qRT-PCR were employed to explore the potential mechanisms of semaglutide.

Semaglutide intervention for 7 d significantly reduced the body weight of BTBR mice (P<0.05), increased the preference index from chamber time (P<0.01) and preference index from sniffing time (P<0.05), elevated the novel object recognition discrimination index (P<0.01), and reduced repetitive stereotyped behaviors such as self-grooming (P<0.001) and marble burying (P<0.01). However, no significant effects on the above mentioned behaviors were observed in C57 mice, and no obvious impact on locomotor activity was demonstrated in the open field test. Network pharmacology analysis identified 78 common targets which enriched in inflammation-related pathways. Semaglutide exhibited favorable binding affinity with potential targets in inflammation-related pathways including Serpine1, Mmp9, Pparg, Stat3, Ppara, and Nr1h3, with binding energies all ≤-4 kcal/mol. qRT-PCR further confirmed that semaglutide intervention significantly downregulated mRNA expression levels of Serpine1, Mmp9, Stat3, Il6, Tnfa, Il17a, and Il1b (P<0.05), and upregulated Pparg expression (P<0.05) in the hippocampus of BTBR mice.

Semaglutide alleviates ASD-like symptoms in BTBR mice by regulating inflammation-related pathways, thus offering a promising potential treatment and foundational research for the clinical management of ASD.