Metabonomic characterization of the 3-nitropropionic acid rat model of Huntington's disease.
3-Nitropropionic acid (3-NP)-induced neurotoxicity can be used as a model for the genetic neurodegenerative disorder Huntington's disease (HD). A metabolic profiling strategy was adopted to explore the biochemical consequences of 3-NP administered to rats in specific brain regions. (1)H NMR spectroscopy was used to characterize the metabolite composition of several brain regions following 3-NP-intoxication. Dose-dependent increases in succinate levels were observed in all neuroanatomical regions, resulting from the 3-NP-induced inhibition of succinate dehydrogenase. Global decreases in taurine and GABA were observed in the majority of brain regions, whereas altered lipid profiles were observed only in the globus pallidus and dorsal striatum. Depleted phosphatidylcholine and elevated glycerol levels, which are indicative of apoptosis, were also observed in the frontal cortex of the 3-NP model. Many of the metabolic anomalies are consistent with those reported in HD. The 3-NP-induced model of HD provides a means of monitoring potential mechanisms of pathology and therapeutic response for drug interventions, which can be efficiently assessed using metabolic profiling strategies.
Tsang
T M
TM
Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics (SORA), Imperial College London, South Kensington, London, SW7 2AZ, UK. t.tsang@imperial.ac.uk
Haselden
J N
JN
Holmes
E
E
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D009574:Nitro Compounds; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010767:Phosphorylcholine / Q000378:metabolism; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000378:metabolism; D013654:Taurine / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D009574:Nitro Compounds; D011422:Propionates; D010767:Phosphorylcholine; D013654:Taurine; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; D019802:Succinic Acid; D002794:Choline; C015392:3-nitropropionic acid