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 Aβ_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 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.

中文翻译：

---

巴马汀通过增强 Aβ 转基因秀丽隐杆线虫的抗氧化防御和小热休克蛋白表达的神经保护作用

巴马汀是一种天然存在的异喹啉生物碱，据报道它对淀粉样蛋白-β-（A β-）诱导的神经毒性具有神经保护作用。然而，巴马汀的神经保护活性的机制在体内的特征仍然很差。我们采用含有人 A β _{1-42的转基因}秀丽隐杆线虫模型来研究巴马汀介导的神经保护作用和可能的机制。用巴马汀治疗显着延迟了麻痹过程并降低了 A β-转基因秀丽隐杆线虫中升高的活性氧水平. 此外，它增加了抗氧化应激能力，而不影响野生型秀丽隐杆线虫的寿命。通路分析表明，差异表达的基因主要与衰老、解毒和脂质代谢有关。实时荧光定量 PCR 表明，抗性相关基因sod-3和shsp显着上调，而脂质代谢相关基因fat-5下调。进一步的研究表明，巴马汀对 A β毒性的抑制作用归因于自由基清除能力和抗性相关基因的表达上调，尤其是shsp，其表达受 HSF-1 调节，在保护细胞免受 A β诱导的毒性中起关键作用。研究表明，与对照线虫相比，用巴马汀处理的转基因 CL2006 线虫中的 A β沉积物显着减少。此外，我们的研究发现，A β诱导的毒性伴随着脂质代谢的失调，导致 A β转基因 CL4176 线虫中过多的脂肪积累。巴马汀对脂质紊乱的缓解不仅应归因于脂肪合成的减少，还应归因于 A β聚集和毒性的抑制，共同维持代谢稳态。这项研究提供了新的见解巴马汀对 A β聚集和毒性的体内神经保护作用，并为预防和治疗 AD 提供有价值的靶点。