Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
J Proteome Res. 2011 Apr 1;10(4):2079-87. doi: 10.1021/pr2000336. Epub 2011 Mar 16.
3-Nitropropionic acid (3-NP), a potent irreversible inhibitor of mitochondrial complex II enzyme, leads to mitochondrial dysfunction and oxidative stress in Huntington's disease (HD) rat model. In this study, biochemical assays were used to demonstrate the presence of oxidative stress and mitochondrial dysfunction in 3-NP early stage HD rat models. Gas chromatography time-of-flight mass spectrometry (GC/TOFMS) was applied to analyze metabolites in brain and plasma of 3-NP-treated and vehicle-dosed rats. The orthogonal partial least-squares discriminant analysis (OPLS-DA) model generated using brain metabolic profiles robustly differentiated the 3-NP early stage HD rat model from the control. Metabonomic characterization of the 3-NP HD rat model facilitated the detection of biomarkers that define the physiopathological phenotype of early stage HD and elucidated the treatment effect of galantamine. Brain marker metabolites that were identified based on the OPLS-DA model were associated with altered glutathione metabolism, oxidative stress, and impaired energy metabolism. The treatment effect of galantamine in early stage HD could not be concluded mechanistically using the brain metabotype. Our study confirmed that GC/TOFMS is a strategic and complementary platform for the metabonomic characterization of 3-NP induced neurotoxicity in the early stage HD rat model.
3-硝基丙酸（3-NP）是一种强效的线粒体复合物 II 酶不可逆抑制剂，可导致亨廷顿病（HD）大鼠模型中线粒体功能障碍和氧化应激。在本研究中，采用生化分析方法证明了 3-NP 早期 HD 大鼠模型中存在氧化应激和线粒体功能障碍。采用气相色谱飞行时间质谱（GC/TOFMS）分析了 3-NP 处理组和对照组大鼠的脑和血浆中的代谢物。基于脑代谢图谱建立的正交偏最小二乘判别分析（OPLS-DA）模型能够将 3-NP 早期 HD 大鼠模型与对照组大鼠区分开来。对 3-NP HD 大鼠模型的代谢组学特征分析有助于检测定义早期 HD 生理病理表型的生物标志物，并阐明加兰他敏的治疗效果。基于 OPLS-DA 模型鉴定的脑标志物代谢物与谷胱甘肽代谢、氧化应激和能量代谢受损有关。使用脑代谢组学不能从机制上推断加兰他敏在早期 HD 中的治疗效果。本研究证实，GC/TOFMS 是用于 3-NP 诱导的早期 HD 大鼠模型神经毒性的代谢组学特征分析的一种具有战略意义的互补平台。
