Glucagon-Like Peptide-1 Receptor Agonists Are Promising for the Treatment of Brain Diseases: an Outlook from the Perspective of Integrative Physiology

Abstract Diabetes is one of the main risk factors for the development of cognitive dysfunction. Insulin resistance and chronic hyperglycemia cause a cascade of pathological events in the brain, including neuroinflammation, impaired neurotransmitter systems and energy metabolism, oxidative stress, and vascular pathologies that ultimately lead to neurodegeneration, loss of synaptic plasticity, brain aging, cognitive impairment, and dementia. The glucagon-like peptide (GLP–1) regulates food consumption and appetite, and its analogs, GLP-1 receptor agonists (GLP-1RAs), are used to treat type 2 diabetes, obesity, and metabolic syndrome. However, an increasing number of research studies are demonstrating that these substances also have neuroprotective effects in neurodegenerative diseases, mental disorders, and other brain conditions. Analysis of the effects of GLP-1 and GLP-1RAs on cognitive, psychometric, cellular, and molecular changes in preclinical and clinical studies shows that these compounds and drugs modulate the molecular and cellular changes that determine the phenomenology of many brain diseases. By activating GLP-1 receptors, natural GLP-1 and GLP-1RAs reduce insulin resistance, suppress neuroinflammation and oxidative stress, and prevent negative changes in neuroplasticity. The review considers the repurposing of GLP-1Ras from the perspective of integrative physiology, summarizes modern concepts about the mechanisms of action of GLP-1RAs according to the results of experimental studies and presents current clinical data on the use of GLP-1RAs in patients with brain diseases. The use of GLP-1RA is a new therapeutic strategy that addresses both metabolic and cognitive/neuropsychiatric aspects, which is fundamentally important for the treatment of comorbid diseases.