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

ABSTRACT

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.