Spinal cord injury (SCI) constitutes a major global health challenge. The pathophysiology of SCI involves many aspects. Current treatments, such as early decompression and glucocorticoids, target single pathways and show limited efficacy with safety concerns. In this context, interventions based on the incretin system are now considered attractive candidates for SCI intervention. This review comprehensively outlines the mechanisms underlying microenvironmental imbalance following SCI and explores glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists as promising options. These agents, recognized for their role in managing diabetes and body weight, demonstrate substantial pleiotropic effects beyond simple glycemic regulation. These beneficial actions include neuroprotection, anti-inflammatory effects, and the promotion of tissue repair. Preclinical SCI studies have indicated that GLP-1 receptor agonists and GIP receptor agonists reduce inflammation by shifting microglia/macrophages to anti-inflammatory phenotypes, suppress apoptosis, increase autophagy, alleviate oxidative stress, promote axonal regeneration, improve the injury microenvironment, and have the potential to regulate immune cells. Related research in other neurological disorders supports these mechanisms, with dual agonists showing superior efficacy. GLP-1 receptor agonists and GIP receptor agonists suggest significant potential to address the multifaceted pathology and associated metabolic complications of SCI. Current evidence highlights the importance of mechanistic elucidation, dose optimization, the development of innovative delivery systems such as nanoparticles, and further validation in large animal and human studies.
