Oral Administration of Astrocyte-Targeted Natural Antioxidants Suppress NOX4-Driven Neuroinflammation and Restore Hippocampal Neurogenesis in MPTP-Induced Parkinson’s Disease Mouse Model

<b>Background/Objectives</b>: Astrocytic redox-inflammatory signaling has been implicated in Parkinson's disease (PD) pathology and may constrain hippocampal neurogenesis. We previously identified an astrocytic NOX4-MPO-OPN axis associated with impaired neurogenic capacity. Here, we tested whether a saffron-derived antioxidant (SDA; <i>Crocus sativus</i> extract) and <i>Passiflora incarnata</i> L. extract (PI) modulate this pathway in an MPTP-induced PD mouse model. <b>Methods</b>: Male C57BL/6J mice were randomized to Sham, MPTP, and treatment groups (<i>n</i> = 9/group for behavior; <i>n</i> = 4-5/group for histology/immunoblotting). SDA or PI (50 mg/kg/day, oral, 5 weeks) was administered, with resveratrol as a positive control. Behavioral, histological, and molecular analyses were performed by investigators blinded to group allocation where feasible. <b>Results</b>: SDA and PI were associated with reduced NOX4/MPO/OPN signals, mainly in GFAP-positive astrocytes, along with recovery of neurogenesis markers (Ki67, DCX, BrdU/NeuN) and synaptic markers (PSD95, synaptophysin), and improved motor performance. Mitochondrial and oxidative injury markers (TIM23, TOM20, OXPHOS subunits; 4-HNE) and apoptotic markers (Bax, cleaved caspase-3, Bcl-2) also shifted toward Sham levels. Given previous reports of Passiflora extracts' sedative effects, we note that metabolic measures (body weight, food intake, and water intake) were similar across groups; however, specific tests for sedation or arousal were not conducted. <b>Conclusions</b>: These findings offer preclinical evidence that SDA and PI modulate redox-inflammatory and mitochondrial stress signatures and are associated with neurogenic, synaptic, and behavioral improvements in an acute MPTP model. Further validation in chronic/genetic PD models and pharmacokinetic/brain exposure studies will be necessary to confirm their translational potential.