Treatment of Parkinson’s Disease with an Anti-Inflammasome NLRP3 Inhibitor Derived from a Natural Product

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder afflicting human health, is primarily characterized by the degeneration of dopaminergic neurons in the midbrain, leading to movement disorders as the main clinical manifestation. Extensive research has demonstrated that the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and its accompanying neuroinflammation play a pivotal role in the progression of PD. ST-4, namely 15-oxosteviol, an analogue of the diterpene oridonin, exhibits potent and specific inhibition of NLRP3 in <i>in vitro</i> experiments. The anti-inflammatory effects of ST-4 were evaluated in mouse models of chronic and progressive disorders, in which it showed significant efficacy in ameliorating obesity, type 2 diabetes, and peritonitis. In this study, the potential interest of ST-4 for the treatment of neuroinflammatory diseases was further investigated in a PD mouse model. ST-4 effectively suppressed the activation of the NLRP3 inflammasome induced by lipopolysaccharide in neuronal cells. Additionally, treatment with ST-4 significantly improved various aspects of PD pathology, including behavioral impairments, loss of dopaminergic neurons, alterations in cerebral neurophysiology, and dysregulated gene expression associated with metabolic dysfunction, highlighting its therapeutic potential for the treatment of Parkinson's disease.