Wang Yong, Zhang Ge-Juan, Sun Yi-Na, Yao Lu, Wang Hui-Sheng, Du Cheng-Xue, Zhang Li, Liu Jian
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an, 710061, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an, 710061, China; Department of Neurology, Xi'an No. 3 Hospital, Xi'an, 710018, China.
Behav Brain Res. 2018 Jul 16;347:175-183. doi: 10.1016/j.bbr.2018.03.020. Epub 2018 Mar 15.
L-DOPA-induced dyskinesia (LID) is a frequent complication of chronic L-DOPA therapy in the clinical treatment of Parkinson's disease (PD). The pathogenesis of LID involves complex molecular mechanisms in the striatum. Metabolomics can shed light on striatal metabolic alterations in LID. In the present study, we compared metabolomics profiles of striatum tissue from Parkinsonian rats with or without dyskinetic symptoms after chronic L-DOPA administration. A liquid chromatography-mass spectrometry based global metabolomics method combined with multivariate statistical analyses were used to detect candidate metabolites associated with LID. 36 dysregulated metabolites in the striatum of LID rats, including anandamide, 2-arachidonoylglycerol, adenosine, glutamate and sphingosine1-phosphate were identified. Furthermore, IMPaLA metabolite set analysis software was used to identify differentially regulated metabolic pathways. The results showed that the metabolic pathways of "Retrograde endocannabinoid signaling", "Phospholipase D signaling pathway", "Glycerophospholipid metabolism" and "Sphingolipid signaling", etc. were dysregulated in LID rats compared to non-LID controls. Moreover, integrated pathway analysis based on results from the present metabolomics and our previous gene expression data in LID rats further demonstrates that aberrant "Retrograde endocannabinoid signaling" pathway might be involved in the development of LID. The present results provide a new profile for the understanding of the pathological mechanism of LID.
左旋多巴诱导的异动症（LID）是帕金森病（PD）临床治疗中慢性左旋多巴治疗常见的并发症。LID的发病机制涉及纹状体中复杂的分子机制。代谢组学能够揭示LID中纹状体的代谢改变。在本研究中，我们比较了慢性给予左旋多巴后有或无异动症症状的帕金森病大鼠纹状体组织的代谢组学图谱。采用基于液相色谱 - 质谱联用的全局代谢组学方法并结合多变量统计分析来检测与LID相关的候选代谢物。在LID大鼠的纹状体中鉴定出36种失调的代谢物，包括花生四烯乙醇胺、2 - 花生四烯酸甘油酯、腺苷、谷氨酸和1 - 磷酸鞘氨醇。此外，使用IMPaLA代谢物集分析软件来鉴定差异调节的代谢途径。结果表明，与非LID对照组相比，LID大鼠中“逆行性内源性大麻素信号传导”、“磷脂酶D信号通路”、“甘油磷脂代谢”和“鞘脂信号传导”等代谢途径失调。此外，基于本代谢组学结果和我们之前关于LID大鼠的基因表达数据进行的综合途径分析进一步表明，异常的“逆行性内源性大麻素信号传导”途径可能参与LID的发生发展。本研究结果为理解LID的病理机制提供了新的视角。
