AGMATINE REDUCES SPINAL GLIAL ACTIVATION AND IMPROVES BEHAVIORAL PERFORMANCE IN METHOTREXATE-TREATED RATS

Methotrexate (MTX), a chemotherapeutic and immunosuppressive drug widely used in oncology and autoimmune diseases, is associated with neurotoxicity that adversely affects motor and cognitive function. Agmatine (AgM), an endogenous neuromodulator, exhibits neuroprotective properties and may contribute to neural tissue preservation and functional recovery. This study investigated the therapeutic efficacy of AgM on MTX-induced behavioral impairments and thoracic spinal cord pathology in rats. Wistar rats (n = 8 per group) were allocated to Control, MTX (37.5 mg/kg once weekly for three consecutive weeks), AgM (40 mg/kg twice daily for seven days), and MTX+AgM groups; in the MTX+AgM group, AgM was administered during the fourth week following completion of the MTX regimen. Behavioral outcomes were quantified using the Morris water maze, open-field, and rotarod paradigms. Thoracic spinal cord integrity was evaluated by luxol fast blue and hematoxylin–eosin staining, and glial activation was assessed using glial fibrillary acidic protein (GFAP) immunohistochemistry. MTX significantly increased escape latency (p < 0.05), reduced target-quadrant occupancy (p < 0.01), and suppressed open-field locomotor activity (p < 0.001), whereas rotarod performance remained unchanged. AgM treatment significantly enhanced open-field locomotor activity compared with MTX alone (p < 0.001). Histopathological analysis revealed pronounced myelin disruption, astroglial deformation, and elevated GFAP immunoreactivity in the MTX group compared with controls (p < 0.001). AgM markedly attenuated GFAP immunoreactivity (p < 0.05) and partially restored spinal tissue organization. These findings indicate that AgM mitigates MTX-induced spinal glial activation and functional impairments, supporting its potential therapeutic value in chemotherapy-associated neurotoxicity.