Miville-Godbout Edith, Bourque Mélanie, Morissette Marc, Al-Sweidi Sara, Smith Tara, Jayasinghe Dushmanthi, Ritchie Shawn, Di Paolo Thérèse
Neuroscience Research Unit, Centre de Recherche du CHU de Québec, CHUL, 2705 Laurier Boulevard, Quebec City, Qc G1V 4G2, Canada; Faculty of Pharmacy, Laval University, 1050, Avenue de la Médecine, Quebec City, Qc G1V 0A6, Canada.
Neuroscience Research Unit, Centre de Recherche du CHU de Québec, CHUL, 2705 Laurier Boulevard, Quebec City, Qc G1V 4G2, Canada.
Brain Res. 2017 Nov 1;1674:70-76. doi: 10.1016/j.brainres.2017.08.020. Epub 2017 Aug 19.
Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson's disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10days with daily oral administration of PPI-1025 (10, 50 or 200mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone.
乙醇胺缩醛磷脂（PlsEtn）是一类甘油磷脂，其特征在于sn-1位存在乙烯基醚键，在膜的结构和功能中起重要作用。先前的报道表明血液和大脑中PlsEtn水平降低与帕金森病（PD）之间存在联系。我们最近报道，含有二十二碳六烯酸（DHA）的缩醛磷脂前体PPI-1011可保护小鼠纹状体多巴胺（DA）免受MPTP毒性。在本文中，我们通过测试含油酸的缩醛磷脂前体PPI-1025进一步研究脂质侧链的特异性要求。雄性小鼠每日口服PPI-1025（10、50或200mg/kg），持续治疗10天。在第5天，小鼠接受MPTP处理，并于第11天处死。PPI-1025处理可防止MPTP诱导的DA和5-羟色胺及其代谢产物的减少。此外，PPI-1025处理可防止MPTP诱导的纹状体多巴胺转运体（DAT）和囊泡单胺转运体2（VMAT2）特异性结合的减少。纹状体DA浓度与DAT或VMAT2特异性结合以及血清缩醛磷脂浓度之间存在显著正相关。PPI-1025的神经保护作用在测试的最高剂量下呈现钟形剂量依赖性丧失效应。含油酸和二十二碳六烯酸（DHA）的缩醛磷脂前体的类似保护反应表明，观察到的神经保护作用不仅归因于DHA，还归因于油酸取代基和缩醛磷脂主链。
