Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660, Boadilla del Monte, Madrid, Spain.
Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660, Boadilla del Monte, Madrid, Spain.
Sci Rep. 2022 Mar 4;12(1):3577. doi: 10.1038/s41598-022-07419-6.
Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival. PTN expression levels are upregulated in the nigrostriatal pathway of Parkinson's Disease (PD) patients. We aimed to characterize the dopaminergic injury and glial responses in the nigrostriatal pathway of mice with transgenic Ptn overexpression in the brain (Ptn-Tg) after intrastriatal injection of the catecholaminergic toxic 6-hydroxydopamine (6-OHDA) at a low dose (5 µg). Ten days after surgery, the injection of 6-OHDA induced a significant decrease of the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and of the striatal TH contents in Wild type (Wt) mice. In contrast, these effects of 6-OHDA were absent in Ptn-Tg mice. When the striatal Iba1 and GFAP immunoreactivity was studied, no statistical differences were found between vehicle-injected Wt and Ptn-Tg mice. Furthermore, 6-OHDA did not cause robust glial responses neither on Wt or Ptn-Tg mice 10 days after injections. In metabolomics studies, we detected interesting metabolites that significantly discriminate the more injured 6-OHDA-injected Wt striatum and the more protected 6-OHDA-injected Ptn-Tg striatum. Particularly, we detected groups of metabolites, mostly corresponding to phospholipids, whose trends were opposite in both groups. In summary, the data confirm lower 6-OHDA-induced decreases of TH contents in the nigrostriatal pathway of Ptn-Tg mice, suggesting a neuroprotective effect of brain PTN overexpression in this mouse model of PD. New lipid-related PD drug candidates emerge from this study and the data presented here support the increasingly recognized "lipid cascade" in PD.
多效蛋白（PTN）是一种参与神经组织修复过程、神经炎症和神经元存活的细胞因子。帕金森病（PD）患者黑质纹状体通路中 PTN 的表达水平上调。我们旨在研究脑中转基因 Ptn 过表达（Ptn-Tg）小鼠黑质纹状体通路中多巴胺能损伤和神经胶质反应，在纹状体中注射低剂量（5μg）儿茶酚胺毒性 6-羟多巴胺（6-OHDA）后 10 天。手术后 10 天，6-OHDA 注射导致 Wt 小鼠黑质中酪氨酸羟化酶（TH）阳性神经元数量和纹状体内 TH 含量显著减少。相比之下，6-OHDA 的这些作用在 Ptn-Tg 小鼠中不存在。当研究纹状体 Iba1 和 GFAP 免疫反应时，在注射载体的 Wt 和 Ptn-Tg 小鼠之间未发现统计学差异。此外，6-OHDA 注射后 10 天，无论是 Wt 还是 Ptn-Tg 小鼠，都不会引起强烈的神经胶质反应。在代谢组学研究中，我们检测到了一些有趣的代谢物，这些代谢物可以显著区分损伤更严重的 6-OHDA 注射 Wt 纹状体和更受保护的 6-OHDA 注射 Ptn-Tg 纹状体。特别是，我们检测到了一组代谢物，它们主要对应于磷脂，其趋势在两组中相反。总之，这些数据证实了 Ptn-Tg 小鼠黑质纹状体通路中 6-OHDA 诱导的 TH 含量下降幅度较低，表明脑 PTN 过表达对该 PD 小鼠模型具有神经保护作用。本研究出现了新的与脂质相关的 PD 药物候选物，并且这里呈现的数据支持 PD 中日益被认可的“脂质级联”。
