Niosomal Mexiletine Attenuates Rotenone-Induced Parkinsonism via Modulation of the circDLGAP4/miR-134-5p/p-CREB Axis and Restoration of Mitochondrial–Autophagic Homeostasis

Background

Parkinson’s disease (PD) is distinguished by progressive dopaminergic degeneration driven by the convergence of oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy. Mexiletine (Mexil), which has demonstrated antioxidant properties, has not been systematically investigated yet for its potential to mitigate mitochondrial-dysfunction-related neurodegeneration in PD. Using an integrated computational and experimental approach, we characterized, for the first time, the neuroprotective mechanisms of Mexil’s action against rotenone (Rot)-induced Parkinsonism and employed niosomes as a nanocarrier platform to enhance mexil delivery and augment its neuroprotective potential in a Parkinson’s disease model.