Luteolin ameliorates neurological deficits and dopaminergic neuronal damage in MPTP-induced Parkinson’s disease mice via regulating the AKT/BNIP3 mitophagy signaling axis

Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Luteolin, a natural dietary flavonoid monomer, exhibits neuroprotective potential; however, its molecular targets and regulatory mechanisms in PD require further exploration. Methods Network pharmacology was employed to predict potential targets of Luteolin against PD. Subsequently, a subacute MPTP-induced PD mouse model was established to evaluate the preventive and therapeutic effects of Luteolin (20, 40, and 100 mg/kg), with levodopa/benserazide serving as a symptomatic pharmacological reference. Motor performance, serum biosafety indicators (ALT, AST, BUN, Cr, CK), pro-inflammatory cytokines, oxidative stress markers, TH-positive neuronal survival, and AKT/BNIP3/LC3 pathway proteins were systematically evaluated. Results Network analysis prioritized AKT1 as a top hub target linking Luteolin to PD pathogenesis. In vivo experiments showed that MPTP intoxication led to severe motor deficits, depletion of SNpc TH-positive neurons (preserving only 43.1% compared with the Normal group, 7.50 ± 1.87 vs. 17.40 ± 2.65 cells/field, P < 0.01), elevated oxidative stress (increased ROS and MDA, decreased SOD), and reduced expression of TH, p-AKT/AKT (decreased by 67.3%), BNIP3 (decreased by 66.7%), and LC3-II/I (all P < 0.01). Luteolin treatment, particularly at medium (40 mg/kg) and high (100 mg/kg) doses, significantly attenuated oxidative stress and central inflammation (TNF-α, IL-1β, IL-6), preserved TH-positive neurons (high-dose preserving 93.1% of control levels, 16.20 ± 2.39 cells/field), and upregulated p-AKT/AKT and BNIP3 protein levels, while serum biochemical parameters of hepatic and renal functions remained within physiological baseline ranges with no significant group differences ( P > 0.05). Conclusion Luteolin confers robust neuroprotection against MPTP neurotoxicity, which is closely associated with anti-inflammatory activity, attenuation of oxidative stress, and positive modulation of AKT/BNIP3 mitophagy-related signaling proteins.