Combined melatonin and edaravone therapy attenuates methylmercury-induced amyotrophic lateral sclerosis-like neurodegeneration through GLP-1 modulation and myelin preservation.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons, resulting in progressive muscle weakness, paralysis, and respiratory failure. Despite the availability of disease-modifying therapies, current treatment options provide only modest clinical benefits, highlighting the need for novel therapeutic strategies targeting multiple pathological mechanisms. Melatonin, a pleiotropic neuroprotective molecule with antioxidant, anti-inflammatory, and anti-apoptotic properties, has emerged as a promising candidate; however, its influence on glucagon-like peptide-1 (GLP-1)-associated neuroprotective signaling and related molecular events in ALS remains poorly understood. Therefore, the present study investigated the neuroprotective efficacy of melatonin in a methylmercury (MTMR)-induced rat model of ALS and explored its effects on GLP-1-associated molecular alterations, neuroinflammation, oxidative stress, apoptosis, neurotransmitter homeostasis, demyelination, and neuronal injury. Molecular docking analysis was performed to predict the interaction of melatonin with proteins implicated in ALS pathology. Adult Wistar rats were exposed to MTMR (5 mg/kg, p.o.) for 21 days to induce ALS-like neurodegeneration, followed by treatment with melatonin (5 or 10 mg/kg, i.p.), edaravone (3 mg/kg, i.p.), or their combination for an additional 21 days. Neurobehavioral performance, biochemical alterations, hematological parameters, molecular biomarkers, and histopathological changes were subsequently evaluated. MTMR administration produced profound motor deficits accompanied by reduced GLP-1 levels, neurotransmitter imbalance, increased neuroinflammatory and apoptotic markers, elevated neurofilament light chain (NEFL), skeletal muscle injury, methylmercury accumulation, and extensive myelin and neuronal damage. Melatonin treatment significantly attenuated these pathological alterations in a dose-dependent manner by increasing GLP-1 levels, improving antioxidant status, reducing inflammatory and apoptotic responses, restoring neurotransmitter balance, preserving myelin integrity, and improving neuronal morphology across multiple brain regions and the spinal cord. Molecular docking further predicted favorable interactions between melatonin and several proteins associated with ALS pathophysiology, supporting its potential as a multitarget therapeutic agent. In most outcome measures, combined treatment with melatonin and edaravone produced greater neuroprotective effects than either intervention alone. Collectively, these findings demonstrate that melatonin substantially attenuates methylmercury-induced ALS-like neuropathology through coordinated modulation of multiple pathological processes associated with neurodegeneration. Although the precise molecular mechanisms require further experimental validation, the observed restoration of GLP-1 levels together with improvements in oxidative stress, neuroinflammation, apoptosis, neurotransmitter homeostasis, and myelin integrity suggests that melatonin may represent a promising adjunctive therapeutic strategy for ALS.