Neuroprotective Effects of Palmatine via the Enhancement of Antioxidant Defense and Small Heat Shock Protein Expression in Aβ‐Transgenic Caenorhabditis elegans

Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-β- (Aβ-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo. We employed transgenic Caenorhabditis elegans models containing human Aβ1-42 to investigate the effects and possible mechanisms of palmatine-mediated neuroprotection. Treatment with palmatine significantly delayed the paralytic process and reduced the elevated reactive oxygen species levels in Aβ-transgenic C. elegans. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type C. elegans. Pathway analysis suggested that the differentially expressed genes were related mainly to aging, detoxification, and lipid metabolism. Real-time PCR indicated that resistance-related genes such as sod-3 and shsp were significantly upregulated, while the lipid metabolism-related gene fat-5 was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on Aβ toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially shsp, whose expression was regulated by HSF-1, played crucial roles in protecting cells from Aβ-induced toxicity. The research showed that there were significantly fewer Aβ deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that Aβ-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in Aβ-transgenic CL4176 nematodes. The alleviation of lipid disorder by palmatine should be attributed not only to the reduction in fat synthesis but also to the inhibition of Aβ aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against Aβ aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.