Luteolin attenuates tramadol-induced parkinsonism-like toxicity by modulating neurotransmitters, neuroinflammation, and GSK-3β signaling in rats.

Parkinsonism is a progressive neurodegenerative condition characterized by dopaminergic neuronal dysfunction, oxidative stress, neuroinflammation, neurotransmitter imbalance, and motor impairment. Chronic tramadol exposure has been reported to induce behavioural and neurochemical alterations resembling Parkinsonism-like neurotoxicity. The present study evaluated the neuroprotective potential of luteolin against tramadol-induced Parkinsonism-like neurotoxicity in rats using levodopa as a standard antiparkinsonian reference drug. Wistar rats were divided into five groups: normal control, tramadol (50 mg/kg, i.p.), luteolin-treated groups (50 and 100 mg/kg, p.o.), and levodopa (10 mg/kg, p.o.). Behavioural assessments were performed using Open Field, Rota Rod, and Narrow Beam Walking tests. Oxidative stress markers, inflammatory cytokines, neurotransmitter levels, and glycogen synthase kinase-3β (GSK-3β) expression were estimated, followed by histopathological evaluation of striatal tissues. Chronic tramadol administration produced significant behavioural deficits, oxidative stress, elevated inflammatory cytokines, neurotransmitter imbalance, and increased GSK-3β expression. Luteolin treatment significantly improved locomotor activity, restored antioxidant defenses, normalized neurotransmitter levels, reduced neuroinflammation, and attenuated GSK-3β expression in a dose-dependent manner. Histopathological findings further confirmed the neuroprotective effect of luteolin. These findings demonstrate that luteolin attenuates tramadol-induced neurobehavioural and neurochemical alterations through modulation of oxidative stress, neuroinflammation, neurotransmitter imbalance, and GSK-3β signaling, suggesting its therapeutic potential against Parkinsonism-like neurodegenerative alterations.