Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.
Neurotox Res. 2022 Dec;40(6):1948-1962. doi: 10.1007/s12640-022-00608-1. Epub 2022 Dec 1.
Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline (Salsolinol, SAL) is a dopamine metabolite that is toxic to dopaminergic neurons in vitro and in vivo, and is involved in the pathogenesis of Parkinson's disease (PD). However, the molecular mechanism by which SAL induces neurotoxicity in PD remains challenging for future investigations. This study found that SAL induced neurotoxicity in SH-SY5Y cells and mice. RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that NLR family pyrin domain-containing 3 (NLRP3)-dependent pyroptosis was enriched by SAL, which was validated by in vitro and in vivo SAL models. Further, NLRP3 inflammasome-related genes (ASC, NLRP3, active caspase 1, IL-1β, and IL-18) were increased at the mRNA and protein level. Acteoside mitigates SAL-induced neurotoxicity by inhibiting NLRP3 inflammasome-related pyroptosis in in vitro and in vivo PD models. In summary, the present study suggests for the first time that NLRP3-dependent pyroptosis plays a role in the pathogenesis of SAL-induced PD, and acteoside mitigates SAL-induced pyroptosis-dependent neurotoxicity in in vitro and in vivo PD models. The present results demonstrated a new mechanism whereby SAL mediates neurotoxicity by activating NLRP3-dependent pyroptosis, further highlighting SAL-induced pyroptosis-dependent neurotoxicity as a potential therapeutic target in PD.
内源性神经毒素 1-甲基-6,7-二羟基-1,2,3,4-四氢异喹啉（Salsolinol，SAL）是一种多巴胺代谢物，在体外和体内对多巴胺能神经元有毒性，并且与帕金森病（PD）的发病机制有关。然而，SAL 诱导 PD 神经毒性的分子机制仍然是未来研究的挑战。本研究发现 SAL 诱导 SH-SY5Y 细胞和小鼠产生神经毒性。使用 RNA 测序（RNAseq）和京都基因与基因组百科全书（KEGG）分析检测 SAL 处理的 SH-SY5Y 细胞中差异表达的基因。我们发现 SAL 富集了 NLR 家族富含吡啶结构域蛋白 3（NLRP3）依赖性细胞焦亡，这在体外和体内 SAL 模型中得到了验证。此外，NLRP3 炎性体相关基因（ASC、NLRP3、活性半胱天冬酶 1、IL-1β 和 IL-18）在 mRNA 和蛋白水平上增加。在体外和体内 PD 模型中，獐牙菜苦苷通过抑制 NLRP3 炎性体相关细胞焦亡减轻 SAL 诱导的神经毒性。综上所述，本研究首次表明，NLRP3 依赖性细胞焦亡在 SAL 诱导的 PD 发病机制中起作用，獐牙菜苦苷减轻体外和体内 PD 模型中 SAL 诱导的细胞焦亡依赖性神经毒性。本研究结果表明，SAL 通过激活 NLRP3 依赖性细胞焦亡介导神经毒性的新机制，进一步强调了 SAL 诱导的细胞焦亡依赖性神经毒性作为 PD 的潜在治疗靶点。
