Therapeutic Efficacy of Curcumin Nanoparticles in Parkinson's Disease: An Integrated Analysis of Network Pharmacology, Experimental Validation, and Gut Microbiota.

Background: Parkinson's disease (PD) ranks as the second most common neurodegenerative condition globally, with a rising occurrence alongside the aging demographic. Previous studies have demonstrated that curcumin monomers can alleviate PD symptoms and slow disease progression, whereas nano-drug delivery systems significantly improve their bioavailability. Notably, gut microbiota imbalance significantly contributes to the onset and advancement of PD; however, the mechanisms by which curcumin nanoparticles produce their therapeutic impact on PD are not yet well understood. Materials and Methods: Initially, network pharmacology was tapped to forecast the probable targets and signaling routes for curcumin in combating Parkinson's Disease. Later on, molecular docking techniques and molecular dynamics experiments were utilized to substantiate its binding effectiveness. Curcumin nanoparticles were synthesized via the emulsion-solvent evaporation technique. After establishing PD models, multidimensional validation was performed using behavioral experiments, serological assays, Western blotting, hematoxylin-eosin staining, and 16S ribosomal RNA (16S rRNA) sequencing. Results: Network pharmacology analysis revealed that curcumin acts through multiple targets and pathways. In vivo experiments demonstrated that curcumin nanoparticles enhanced motor capabilities in Parkinson's disease mice, bolstered antioxidant enzyme levels, alleviated oxidative stress, and inhibited neuronal apoptosis via the Akt signaling pathway. Histopathological analysis showed significant improvements in the number and arrangement of neurons in the hippocampal dentate gyrus (DG) region. Furthermore, remodeling of the gut microbiota and metabolic regulation alleviated neuroinflammation and enhanced neuroprotection. Conclusion: Curcumin nanoparticles inhibit neuronal apoptosis by activating the Akt signaling pathway and, while also remodeling the gut microbiota microenvironment, collectively ameliorate PD pathology. This study provides pharmacological evidence that curcumin nanoparticle therapy mediates its therapeutic actions through multiple mechanisms, and identifies potential therapeutic targets for PD treatment.