Semaglutide, a novel glucagon-like peptide-1 agonist, amends experimental autoimmune encephalomyelitis-induced multiple sclerosis in mice: Involvement of the PI3K/Akt/GSK-3β pathway

• Published in: International immunopharmacology 2023-02, Vol.115, p.109647, Article 109647
• Main Authors: Sadek, Mohamed A, Kandil, Esraa A, El Sayed, Nesrine S, Sayed, Helmy M, Rabie, Mostafa A
• Format: Article
• Language: English
• Subjects: Animals; BDNF; EAE; Encephalomyelitis, Autoimmune, Experimental - pathology; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta - metabolism; GSK-3β; Mice; Mice, Inbred C57BL; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - pathology; Neurodegenerative Diseases; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt; Proto-Oncogene Proteins c-akt - metabolism; Semaglutide; Signal Transduction
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109647

•Semaglutide protects mice from EAE-induced cognitive and motor impairments.•Semaglutide activates the ramified PI3K/Akt/GSK-3β pathway.•GSK-3β inhibition amends neurodegeneration, oxidative stress, and neuroinflammation.•Semaglutide conquers demyelination and augments remyelination via the CREB/BDNF axis.•Semaglutide elevates Nrf2 levels, exerting antioxidant and anti-inflammatory effects. Multiple sclerosis (MS) is a disabling neurodegenerative disease that causes demyelination and axonal degeneration of the central nervous system. Current treatments are partially effective in managing MS relapses and have a negligible impact on treating MS cognitive deficits and cannot enhance neuronal remyelination, imposing a need for a new MS remedy. Semaglutide, a novel glucagon-like peptide-1 agonist, has recently displayed a neuroprotective effect on several neurodegenerative diseases, suggesting that it may have a protective effect in MS. Therefore, this study was conducted to investigate the influence of semaglutide on experimental autoimmune encephalomyelitis (EAE)-induced MS in mice. Here, EAE was induced in mice using spinal cord homogenate, which eventually altered the mice’s cognitive and motor functions, similar to what is observed in MS. Interestingly, intraperitoneally administered semaglutide (25 nmol/kg/day) amended EAE-induced cognitive and motor deficits observed in novel object recognition, open field, rotarod, and grip strength tests. Moreover, histological examination revealed that semaglutide treatment attenuated hippocampal damage and corpus callosum demyelination caused by EAE. Additionally, biochemical testing revealed that semaglutide activates the PI3K/Akt axis, which eventually hampers GSK-3β activity. GSK-3β activity inhibition attenuates demyelination and triggers remyelination through CREB/BDNF; furthermore, it boosts Nrf2 and SOD levels, protecting the mice from EAE-induced oxidative stress. Additionally, GSK-3β inhibition minimizes neuroinflammation, as reflected by decreased NF-kβ and TNF-α levels. In conclusion, semaglutide has a neuroprotective effect in EAE-induced MS in mice, which is mediated by activating the ramified PI3K/Akt/GSK-3β pathway.