L‐Carnitine Attenuates Methotrexate‐Induced Cortical Neurotoxicity via Glial and Apoptotic Pathways

Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent, but its clinical application is limited by dose-dependent neurotoxicity, particularly in the cerebral cortex. MTX-induced injury involves oxidative imbalance, mitochondrial dysfunction, glial activation, and apoptosis. L-carnitine (LCR), a mitochondrial cofactor with antioxidant and antiapoptotic properties, has been proposed as a potential neuroprotective agent. This study investigated whether LCR could attenuate MTX-induced cortical damage in rats. Twenty-four female Wistar rats were randomly assigned to four groups (n = 6): control, MTX, LCR, and MTX + LCR. MTX (20 mg/kg, i.p.) was given on Day 5, whereas LCR (200 mg/kg, i.p.) was administered daily for 10 days. Cortical tissue was evaluated histopathologically, immunohistochemically for GFAP and OLIG2, and by qRT-PCR for BAX and BCL2 expression. MTX caused severe cortical degeneration, perivascular edema, reactive astrogliosis, oligodendroglial activation, and a significant increase in the BAX/BCL2 ratio. LCR co-treatment markedly reduced histological injury, attenuated glial activation, and restored apoptotic balance toward cell survival. LCR alone showed no adverse effects compared with controls. These findings demonstrate that LCR provides effective neuroprotection against MTX-induced cortical injury in rats.