Intranasal stromal cell-derived factor-1α mitigates parkinsonian deficits via dual modulation of neuroinflammation...

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and neuroinflammation, with emerging evidence implicating gut-brain axis dysregulation in its pathogenesis. Stromal cell-derived factor-1α (SDF-1α), a chemokine with neuroprotective properties, remains underexplored as a therapeutic agent for PD. This study investigates the efficacy of intranasal SDF-1α administration in mitigating motor deficits, gastrointestinal (GI) dysfunction, and neuroinflammation, and its concurrent effects on the gut microbiota in an MPTP-induced PD mouse model. Male C57BL/6J mice were divided into vehicle, MPTP, and MPTP + SDF-1α groups. Behavioral assessments, including the rotarod test and grip strength test, demonstrated that SDF-1α significantly attenuated MPTP-induced motor impairments, including bradykinesia and coordination deficits. Immunofluorescence analysis revealed that SDF-1α restored tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra (SN), indicating robust dopaminergic neuroprotection. Furthermore, SDF-1α ameliorated GI dysfunction by reducing intestinal permeability, as measured by FITC-dextran assay, and improving gut motility, as assessed by Evans blue transit test. Mechanistically, SDF-1α suppressed nigrostriatal inflammation by reducing pro-inflammatory cytokines (IL-6, TNF-α) while elevating anti-inflammatory markers (IL-4, IL-10). Activation of astrocytes (GFAP+) in MPTP-treated mice was reduced to near-control levels following SDF-1α administration. Gut microbiota analysis via 16S rRNA sequencing revealed that SDF-1α restored both α- and β-diversity, counteracting MPTP-induced dysbiosis. Notably, SDF-1α reversed the depletion of Akkermansia, a keystone genus associated with mucosal integrity and barrier function. These findings demonstrate that intranasal SDF-1α concurrently attenuates motor and gastrointestinal deficits, nigrostriatal neuroinflammation, intestinal barrier disruption, and gut microbiota dysbiosis in the MPTP mouse model. Our study highlights the microbiota-gut-brain axis as a critical therapeutic target in PD and proposes intranasal SDF-1α delivery as a novel, non-invasive strategy warranting further mechanistic investigation.