Semaglutide slows the progression of cognitive impairment and pathological changes in the hippocampus in a model of Alzheimer's disease

Currently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are considered promising drugs for the treatment of Alzheimer's disease (AD) and other neurodegenerative diseases due to their complex mechanism of action, which includes (in addition to general somatic effects) an impact on neuroplasticity. This necessitates a detailed study of drugs in this group using appropriate informative experimental models.

Objective: to characterise the effect of semaglutide, one of the main representatives of the GLP-1RAs class, on the development of neurodegenerative processes in the hippocampus and cognitive impairments in animals with a streptozocin (STZ) model of AD.

Material and methods. Streptozocin at a dose of 3 mg/kg was administered into the lateral ventricles of Wistar rats, and semaglutide at a dose of 0.1 mg/kg was administered intraperitoneally (every other day for 5 weeks). The behaviour of the animals was assessed in the ‘Novel Object Recognition’ and ‘T-Maze’ tests. Nine weeks after discontinuation of the drug, immunomorphological methods were used to determine the effect of semaglutide on neurodegenerative processes in the CA3 field of the hippocampus.

Results. Streptozocin caused impaired recognition of a new object and increased the latency period for entering the closed arm of the T-maze, as well as leading to tau protein accumulation and mitochondrial and synaptic abnormalities in the CA3 field of the hippocampus. Semaglutide significantly attenuated streptozocin-induced memory impairment and depression-like behaviour and improved morphological indicators of synaptic integrity (based on the detection of synaptophysin and PSD95 proteins) neuronal energy metabolism (as determined by the detection of glycolysis and oxidative phosphorylation enzymes), and reduced tau protein phosphorylation.

Conclusion. In a model of sporadic AD, semaglutide has been shown to attenuate cognitive impairment in laboratory animals and reduce the severity of morphological abnormalities in the CA3 region of the hippocampus, with the neuroprotective effect of the drug persisting after discontinuation of therapy.

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