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 - (A β -) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo . We employed transgenic Caenorhabditis elegans models containing human A β 1-42 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 A β -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 A β 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 A β -induced toxicity. The research showed that there were significantly fewer A β deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that A β -induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in A β -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 A β aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against A β aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.