Serial 1H-NMR Spectroscopy Study of Metabolic Impairment in Primates Chronically Treated with the Succinate Dehydrogenase Inhibitor 3-Nitropropionic Acid

• Published in: Neurobiology of disease Vol. 6; no. 4; pp. 259 - 268
• Main Authors: Dautry, Caroline, Condé, Francoise, Brouillet, Emmanuel, Mittoux, Vincent, Beal, M.Flint, Bloch, Gilles, Hantraye, Philippe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.1999; Elsevier
• Subjects: 3-nitropropionic acid, baboon; Animals; Aspartic Acid - analogs & derivatives; Aspartic Acid - metabolism; Body Water - metabolism; Cell Count; choline; Choline - metabolism; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Creatine - metabolism; Huntington's disease; Immunohistochemistry; lactate; Lactic Acid - metabolism; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; N-acetylaspartate; neurodegeneration; Nitro Compounds; Occipital Lobe - drug effects; Occipital Lobe - metabolism; Papio; Phosphocreatine - metabolism; phosphocreatine/creatine; Propionates - toxicity; Putamen - drug effects; Putamen - metabolism; Putamen - pathology; quantitative 1H-MRS; Succinate Dehydrogenase - antagonists & inhibitors; Time Factors; quantitative 1H-MRS; choline; neurodegeneration; 3-nitropropionic acid, baboon; lactate; Huntington's disease; phosphocreatine/creatine; N-acetylaspartate
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1006/nbdi.1999.0244

Previous studies in primates have shown that chronic systemic administration of the succinate dehydrogenase (SDH) inhibitor, 3-nitropropionic acid (3NP), replicates most of the motor, cognitive, and histopathological features of Huntington's disease. In the present study, serial 1H-NMR spectroscopy (1H-MRS) assessment of striatal and occipital cortex concentrations of N-acetylaspartate, phosphocreatine/creatine, choline, and lactate, were obtained every 2-weeks during the entire course of a chronic 3NP treatment in baboons. A region-selective increase in lactate was detected in the striatum of the 3NP-treated animals, either immediately before or in conjunction with a lesion in the dorsolateral putamen detected by T2-MR imaging. Absolute 1H-MRS quantitation demonstrated a progressive and region-specific decrease in striatal N-acetylaspartate, creatine, and choline, occuring as early as 3 weeks before the first detection of lactate. These results demonstrate that 1H-MRS can be used to monitor early stages of brain metabolic impairment. In addition, given that 3NP-induced SDH inhibition following systemic injection similarly affects all brain regions, the striatal selective decreases in N-acetylaspartate or creatine concentrations are not simply related to the level of mitochondrial impairment but to a preferential vulnerability of the striatum to 3NP-induced toxicity.