Neuroprotective Effects of Palmatine via the Enhancement of Antioxidant Defense and Small Heat Shock Protein Expression in A<i>β</i>‐Transgenic <i>Caenorhabditis elegans</i>

Abstract

Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-<i>β</i>- (A<i>β</i>-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized <i>in vivo</i>. We employed transgenic <i>Caenorhabditis elegans</i> models containing human A<i>β</i> _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<i>β</i>-transgenic <i>C. elegans</i>. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type <i>C. elegans</i>. 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 <i>sod-3</i> and <i>shsp</i> were significantly upregulated, while the lipid metabolism-related gene <i>fat-5</i> was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on A<i>β</i> toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially <i>shsp</i>, whose expression was regulated by HSF-1, played crucial roles in protecting cells from A<i>β</i>-induced toxicity. The research showed that there were significantly fewer A<i>β</i> deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that A<i>β</i>-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in A<i>β</i>-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<i>β</i> aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the <i>in vivo</i> neuroprotective effects of palmatine against A<i>β</i> aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.