Saffron-Derived Antioxidant and Passiflora incarnata L. Extract Preserve Cerebellar Fetuin-A and Protect Purkinje Cells Against MPTP/MPP+-Induced Injury

Oxidative stress contributes to neuronal injury in Parkinson’s disease (PD), and the cerebellum is increasingly recognized as an affected region. We previously reported that Fetuin-A (alpha-2-HS-glycoprotein) is reduced in cerebellar Purkinje cells in human PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that silencing it reduces Purkinje cell survival without apoptosis. We asked whether this reduction is pharmacologically modifiable by saffron-derived antioxidant (SDA) and Passiflora incarnata L. extract (PIE). SDA and PIE were administered orally at 50 mg/kg/day for 5 weeks to MPTP-treated C57BL/6J mice, with resveratrol (RES) as a comparator. In 1-methyl-4-phenylpyridinium (MPP+)-challenged primary cerebellar neurons, SDA and PIE were tested at 25 µg/mL and RES at 200 µg/mL. MPTP lowered nigral tyrosine hydroxylase immunoreactivity, grip strength, rotarod performance, Purkinje cell density and cerebellar Fetuin-A and raised cleaved caspase-3, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Fluoro-Jade C signals. SDA and PIE attenuated all these changes. In vitro, MPP+ raised 2′,7′-dichlorofluorescin diacetate (DCFDA) fluorescence and lowered Fetuin-A, and all three treatments reduced DCFDA fluorescence and restored Fetuin-A. Annexin V/propidium iodide (PI) profiling showed a substantial Annexin V−/PI+ necrotic component at 24 h, consistent with our earlier knockdown data. Cerebellar Fetuin-A emerges as a treatment-responsive correlate of Purkinje cell integrity.