GLP-1 receptor agonists show neuroprotective potential through metabolic and inflammatory pathways, but clinical efficacy in neurological diseases remains inconsistent.

Neurological diseases, including neurodegeneration, cerebrovascular pathology, and metabolism-related brain disorders, are driven by convergent mechanisms such as metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury. Current standard-of-care often addresses symptoms rather than underlying pathology. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, modulate many of these pathways. The expression of GLP-1 receptors in neurons, glial cells, and the neurovascular unit provides a strong biological rationale for exploring their neuroprotective potential.

This review synthesized experimental and clinical evidence on the mechanisms and therapeutic prospects of GLP-1RAs in neurological diseases. It analyzed studies exploring how GLP-1RAs modulate key pathological processes like metabolic dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neurovascular injury across systemic and central compartments. The review also assessed clinical trial outcomes in conditions such as Parkinson's disease and Alzheimer's disease, considering factors that might contribute to observed inconsistencies in clinical findings.

Preclinical studies consistently suggest that GLP-1RAs can reduce neuroinflammation and oxidative stress, support mitochondrial function, and help maintain blood-brain barrier integrity. These actions are mediated through GLP-1 signaling in neurons and glial cells. > However, clinical findings remain inconsistent: studies in Parkinson's disease have reported encouraging signals, but biomarker evidence for disease modification is still limited. In Alzheimer's disease, clinical trials have produced mixed or negative results. These discrepancies may reflect critical factors such as disease stage, patient selection, drug-specific pharmacology, central nervous system exposure, endpoint sensitivity, and treatment duration.