New Insights on the Potential Role of Pyroptosis in Parkinson's Neuropathology and Therapeutic Targeting of NLRP3 Inflammasome with Recent Advances in Nanoparticle-Based miRNA Therapeutics.

Parkinson's disease (PD) is a widespread neurodegenerative disorder characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). This review aims to summarize the recent advancements in the pathophysiological mechanisms of pyroptosis, mediated by NLRP3 inflammasome, in advancing PD and the anti-pyroptotic agents that target NLRP3 inflammatory pathways and miRNA. PD pathophysiology is primarily linked to the aggregation of α-synuclein, the overproduction of reactive oxygen species (ROS), and the development of neuroinflammation due to microglial activation. Prior research indicated that a significant quantity of microglia is activated in both PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models, triggering neuroinflammation and resulting in a cascade of cellular death. Microglia possess an inflammatory complex pathway termed the nucleotide-binding oligomerization domain-, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome. Activation of the NLRP-3 inflammasome results in innate cytokines maturation, including IL-18 and IL-1β, which initiates the neuroinflammatory signal and induces a type of inflammatory cell death known as pyroptosis. Upon neuronal damage, intracellular levels of damage-associated molecular patterns (DAMPs), including reactive oxygen species (ROS), would build. DAMPs induce unregulated cell death and subsequent release of oxidative intermediates and pro-inflammatory cytokines, leading to the progression of PD. Thus, targeting of neuroinflammation using antipyroptotic medications can be efficiently achieved by blocking NLRP3 and obstructing IL-1β signaling and release. Furthermore, many research studies showed that miRNAs have been identified as regulators of the NLRP3 inflammasome and Nrf2 signal, which subsequently modulate the NLRP3-Nrf2 axis in PD. Nanotechnology promises potential for the advancement of miRNA-based therapies. Nanoparticles that ensure miRNA stability, traverse the blood-brain barrier (BBB) and distribute miRNA targeting regions needed to be created. In conclusion, targeting the pyroptosis pathway via NLRP3 or miRNA may serve as a prospective therapeutic strategy for PD in the future.