Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Neurochem Res. 2021 Sep;46(9):2226-2237. doi: 10.1007/s11064-021-03359-1. Epub 2021 May 20.
The mechanisms underlying propofol-induced toxicity in developing neurons are still unclear. The aim of present study was to explore the role of Pink1 mediated mitochondria pathway in propofol-induced developmental neurotoxicity. The primary Neural Stem Cells (NSCs) were isolated from the hippocampus of E15.5 mice embryos and then treated with propofol. The effects of propofol on proliferation, differentiation, apoptosis, mitochondria ultrastructure and MMP of NSCs were investigated. In addition, the abundance of Pink1 and a group of mitochondria related proteins in the cytoplasm and/or mitochondria were investigated, which mainly included CDK1, Drp1, Parkin1, DJ-1, Mfn1, Mfn2 and OPA1. Moreover, the relationship between Pink1 and these molecules was explored using gene silencing, or pretreatment with protein inhibitors. Finally, the NSCs were pretreated with mitochondrial specific antioxidant (MitoQ) or Drp1 inhibitor (Mdivi-1), and then the toxic effects of propofol on NSCs were investigated. Our results indicated that propofol treatment inhibited NSCs proliferation and division, and promoted NSCs apoptosis. Propofol induced significant NSCs mitochondria deformation, vacuolization and swelling, and decreased MMP. Additional studies showed that propofol affected a group of mitochondria related proteins via Pink1 inhibition, and CDK1, Drp1, Parkin1 and DJ-1 are the important downstream proteins of Pink1. Finally, the effects of propofol on proliferation, differentiation, apoptosis, mitochondrial ultrastructure and MMP of NSCs were significantly attenuated by MitoQ or Mdivi-1 pretreatment. The present study demonstrated that propofol regulates the proliferation, differentiation and apoptosis of NSCs via Pink1mediated mitochondria pathway.
丙泊酚诱导发育期神经元毒性的机制尚不清楚。本研究旨在探讨Pink1 介导的线粒体途径在丙泊酚诱导发育性神经毒性中的作用。原代神经干细胞（NSCs）从 E15.5 小鼠胚胎海马中分离出来，然后用丙泊酚处理。研究了丙泊酚对 NSCs 增殖、分化、凋亡、线粒体超微结构和 MMP 的影响。此外，还研究了细胞质和/或线粒体中 Pink1 和一组与线粒体相关的蛋白质的丰度，主要包括 CDK1、Drp1、Parkin1、DJ-1、Mfn1、Mfn2 和 OPA1。此外，还通过基因沉默或蛋白抑制剂预处理来探索 Pink1 与这些分子之间的关系。最后，用线粒体特异性抗氧化剂（MitoQ）或 Drp1 抑制剂（Mdivi-1）预处理 NSCs，然后研究丙泊酚对 NSCs 的毒性作用。结果表明，丙泊酚处理抑制 NSCs 增殖和分裂，促进 NSCs 凋亡。丙泊酚诱导 NSCs 线粒体明显变形、空泡化和肿胀，MMP 降低。进一步的研究表明，丙泊酚通过抑制 Pink1 影响一组与线粒体相关的蛋白质，而 CDK1、Drp1、Parkin1 和 DJ-1 是 Pink1 的重要下游蛋白。最后，MitoQ 或 Mdivi-1 预处理显著减轻了丙泊酚对 NSCs 增殖、分化、凋亡、线粒体超微结构和 MMP 的影响。本研究表明，丙泊酚通过 Pink1 介导的线粒体途径调节 NSCs 的增殖、分化和凋亡。
