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Metabonomic Characterization of the 3-Nitropropionic Acid Rat Model of Huntington’s Disease

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Abstract

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. 1H 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.

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Abbreviations

NAA:

N-Acetylaspartate

CPMG:

Carr–Purcell–Meiboom–Gill

FID:

Free induction decay

GFAP:

Glial fibrillary acid protein

HD:

Huntington’s disease

H&E:

Haematoxylin and eosin

HR MAS 1H NMR:

High-resolution magic angle spinning proton nuclear magnetic resonance spectroscopy

3-NP:

3-Nitropropionic acid

SDH:

Succinate dehydrogenase

TCA:

Tricarboxylic acid cycle

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Authors and Affiliations

  1. Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics (SORA), Faculty of Medicine, Imperial College London, SAF Building, Imperial College Road, South Kensington, London, SW7 2AZ, UK

    T. M. Tsang & E. Holmes

  2. Investigative Preclinical Toxicology, Safety Assessment, GlaxoSmithKline Research & Development, Park Road, Ware, Herts, SG12 0DP, UK

    J. N. Haselden

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Tsang, T.M., Haselden, J.N. & Holmes, E. Metabonomic Characterization of the 3-Nitropropionic Acid Rat Model of Huntington’s Disease. Neurochem Res 34, 1261–1271 (2009). https://doi.org/10.1007/s11064-008-9904-5

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