Dynamin-Related Protein 1 and the NLRP3 Inflammasome in Parkinson's Disease: Mechanistic Insights and Therapeutic Opportunities.

Abstract

Introduction: Parkinson's disease (PD) is characterized by the progressive destruction of the dopaminergic cells in the substantia nigra region. The incidence of PD continues to rise, with over 8.5 million people affected in 2019 and projections indicating it could reach over 17 million by 2040 compared with levels observed since 1980. This review examines the mechanistic role of Dynamin-Related Protein 1 (Drp1) and Nod-Like Receptor Family Pyrin Domain-Containing 3 (NLRP3) inflammasome in the development and pathogenesis of PD.

Methods: The information was collected from databases such as PubMed, Embase, Google Scholar, Web of Science, and Elsevier database.

Results: There is a potential for Drp1 and NLRP3 pathways to serve as therapeutic targets in PD. Drp1 inhibitors, such as Mdivi-1, aid in mediating mitochondrial homeostasis, and NLRP3 inhibitors prevent inflammation. Natural compounds that modulate such pathways include resveratrol and curcumin, and preclinical models demonstrate multi-target neuroprotection via direct antioxidant and anti-inflammatory properties.

Discussion: The intricate relationship among oxidative stress, mitochondrial dynamics and inflammation indicates that a combination drug therapy approach is more likely to be effective compared to a single-agent strategy. In a subsequent phase, there is a need for improved formulation and enhancement of natural compounds to maximize their bioavailability and efficacy, particularly in terms of selective Drp1 and NLRP3 inhibitors.

Conclusion: The Drp1-NLRP3 axis is one of the essential mechanistic connections between mitochondrial dynamics and neuroinflammation in PD. Focusing on this axis could offer novel therapeutic options, and advancing these approaches could pave the way for therapies that not only alleviate symptoms but also slow or halt the progression of the disease.