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Apoptosis, oxidative stress, and neuroinflammation have been linked to the onset of Parkinson's disease (PD). Although the pre-treatment effects of Silibinin on a PD model have been evaluated, in the current study we investigated the chronic therapeutic effects of Silibinin microinjection on a rat model of established parkinsonism along with behavioral and laboratory markers assessments.Parkinsonism was induced by 6-hydroxydopamine (6-OHDA, 8 μg/2μl/rat). 21 days after that, animals were treated with Silibinin (100, 200, and 300 mg/kg for 15 consecutive days). Every two days, the bar test was used to evaluate Silibinin's anti-cataleptic properties. At the end, myeloperoxidase (MPO) activity and toll-like receptor 4 (TLR4) expression in the substantia nigra pars compacta (SNc), along with cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, caspase-3, Bax and Bcl-2 levels were assessed. We used homology modeling to predict the 3D structure of TLR4.Silibinin's Chronic treatment, dose-dependently decreased catalepsy. MPO activity and levels of TNF-α, IL-6, and IL-1β were reduced in Silibinin-treated rats in all three doses. Silibinin decreased Bax/Bcl-2 ratio, caspase-3, and downregulated TLR4 expression. Molecular docking revealed that there were hydrophobic and hydrogen bond interactions between the studied ligand and TLR4. Silibinin formed a stable complex with both monomer and dimer forms of TLR4.In accordance with molecular modeling and alleviation of TLR4 activity with a consequent reduction in oxidative stress, restoration of CSF inflammatory cytokine, and minimization of SNc neuronal apoptosis, long-term therapy with Silibinin offers a potential opportunity for symptomatic PD treatment.