Serial 1H-NMR spectroscopy study of metabolic impairment in primates chronically treated with the succinate dehydrogenase inhibitor 3-nitropropionic acid.
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.
Dautry
C
C
URA CEA CNRS 2210, Groupe RMN, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 4 place Gal Leclerc, Orsay Cedex, 91401, France.
Condé
F
F
Brouillet
E
E
Mittoux
V
V
Beal
M F
MF
Bloch
G
G
Hantraye
P
P
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001834:Body Water / Q000378:metabolism; D002452:Cell Count; D002794:Choline / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003401:Creatine / Q000378:metabolism; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D009574:Nitro Compounds; D009778:Occipital Lobe / Q000187:drug effects / Q000378:metabolism; D010215:Papio; D010725:Phosphocreatine / Q000378:metabolism; D011422:Propionates / Q000633:toxicity*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D009574:Nitro Compounds; D011422:Propionates; D010725:Phosphocreatine; D001224:Aspartic Acid; D019344:Lactic Acid; C000179:N-acetylaspartate; D013385:Succinate Dehydrogenase; D003401:Creatine; D002794:Choline; C015392:3-nitropropionic acid