Beyond Glycemic Control: The Pleiotropic Role of GLP-1RAs and Melatonin in Combating Neuroinflammation and Mitochondrial Dysfunction

Mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired protein homeostasis form interconnected pathological networks in acute central nervous system injury and chronic neurodegenerative disease. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for metabolic disorders, exhibit neuroprotective activity in experimental models through effects on neuronal survival, metabolic adaptation, and inflammatory signaling. Melatonin complements these actions through mitochondrial redox protection, preservation of bioenergetics, and circadian regulation. This narrative review examines the pharmacological diversity and central nervous system accessibility of GLP-1RAs, including emerging multi-receptor agonists, and their convergence with melatonin on AMPK, sirtuin–PGC-1α, and mitochondrial quality-control networks. Evidence from stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes-associated cognitive decline highlights opportunities to translate these mechanisms into neuroprotective strategies. Experimental efficacy, exploratory cognitive findings, and existing clinical experience provide a foundation for further investigation, while heterogeneous clinical outcomes help define appropriate populations, endpoints, and treatment conditions. A mitochondrial-support framework is proposed in which melatonin may preserve the cellular environment needed for GLP-1RA-mediated metabolic and survival responses. Together, these complementary mechanisms provide a promising foundation for developing combined GLP-1RA–melatonin strategies to preserve mitochondrial function, attenuate neuroinflammation, and support cognitive and functional recovery.