Curcumin Alleviates Methotrexate‐Induced Neurobehavioral Deficits and Modulates the Redox–Inflammatory–Neurotrophic Axis in Mice

Methotrexate (MTX), a widely used chemotherapeutic agent, is associated with central nervous system toxicity characterized by oxidative stress, neuroinflammation, and behavioral disturbances. The present study investigated whether curcumin mitigates MTX-induced neurotoxicity by modulating redox balance and inflammatory-neurotrophic signaling pathways. Twenty-four male BALB/c mice were randomly assigned to four groups: control, MTX (40 mg/kg, single intraperitoneal dose), MTX+curcumin (50 mg/kg oral pretreatment), and curcumin alone. Behavioral alterations were assessed using the open field, elevated plus maze, and tail suspension tests. Serum and hippocampal levels of tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were quantified. MTX administration induced significant anxiety- and depression-like behaviors, elevated TNF-α levels, increased TOS and OSI, and reduced TAS and BDNF in both serum and hippocampal tissue (respectively, p < 0.05 and p < 0.001). Curcumin pretreatment markedly attenuated these alterations, restoring redox homeostasis, suppressing TNF-α overexpression, and normalizing BDNF levels. Behavioral improvements paralleled biochemical recovery, particularly within hippocampal tissue. In conclusion, our data indicate that curcumin attenuates MTX-induced neurobehavioral deficits and biochemical alterations. The protective effects of curcumin are likely mediated, at least in part, by restoring redox homeostasis and modulating TNF-α/BDNF signaling, suggesting a potential therapeutic avenue for mitigating chemotherapy-induced neurotoxicity.