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. Methods: Molecular docking identified candidate molecular targets underlying niosomal Mexil’s neuroprotective potential. Sprague–Dawley male rats were assigned to control, Rot, and Rot plus niosomal Mexil (30 and 50 mg/kg) groups. Motor performance was evaluated, while dopaminergic degeneration, oxidative stress, neuroinflammation, mitochondrial dysfunction, and autophagy were assessed biochemically, histopathologically, and immunohistochemically. Results: Docking revealed promising interactions between Mexil and both phosphorylated cAMP response element-binding protein (p-CREB) and alpha-synuclein, with binding scores of −5.2 and −4.9 kcal/mol, respectively. Niosomal Mexil improved motor function, restored dopamine and tyrosine hydroxylase levels, and curtailed alpha-synuclein accumulation. Most notably, niosomal Mexil engaged a previously unexplored circular RNA DLGAP4/microRNA-134-5p/p-CREB axis, promoted mitochondrial biogenesis via the phosphorylated AMP-activated protein kinase (p-AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/sirtuin-1 (SIRT-1) pathway, and rebalanced mitochondrial dynamics. These changes were accompanied by restored autophagic axis and suppressed oxidative stress and inflammation. Conclusions: Niosomal Mexil confers neuroprotection against Rot-induced Parkinsonism by orchestrating oxidative, mitochondrial, autophagic, and inflammatory pathways, positioning it as a mechanistically novel disease-modifying candidate warranting further preclinical evaluation in PD.