title: Metabolic profiling of 3-nitropropionic acid early-stage Huntington's disease rat model using gas chromatography time-of-flight mass spectrometry.
abstract: 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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors.forename: Kai Lun
authors.initials: KL
authors.lastname: Chang
authors.forename: Lee Sun
authors.initials: LS
authors.lastname: New
authors.forename: Mainak
authors.initials: M
authors.lastname: Mal
authors.forename: Catherine W
authors.initials: CW
authors.lastname: Goh
authors.forename: Chiu Cheong
authors.initials: CC
authors.lastname: Aw
authors.forename: Edward R
authors.initials: ER
authors.lastname: Browne
authors.forename: Eric C Y
authors.initials: EC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors; D005702:Galantamine / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods*; D006816:Huntington Disease / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D008928:Mitochondria / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D018697:Nootropic Agents / Q000494:pharmacology; D018384:Oxidative Stress; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009574:Nitro Compounds; D018697:Nootropic Agents; D011422:Propionates; D005702:Galantamine; D042963:Electron Transport Complex II; C015392:3-nitropropionic acid