Early N-acetylaspartate depletion is a marker of neuronal dysfunction in rats and primates chronically treated with the mitochondrial toxin 3-nitropropionic acid.
N-acetylaspartate (NAA) quantification by 1H-magnetic resonance spectroscopy has been commonly used to assess in vivo neuronal loss in neurodegenerative disorders. Here. the authors used ex vivo and in vivo 1H-magnetic resonance spectroscopy in rat and primate models of progressive striatal degeneration induced by the mitochondrial toxin 3-nitropropionate (3NP) to determine whether early NAA depletions could also be associated with neuronal dysfunction. In rats that were treated for 3 days with 3NP and had motor symptoms, the authors found a significant decrease in NAA concentrations, specifically restricted to the striatum. No cell loss or dying cells were found at this stage in these animals. After 5 days of 3NP treatment, a further decrease in striatal NAA concentrations was observed in association with the occurrence of dying neurons in the dorsolateral striatum. In 3NP-treated primates, a similar striatal-selective and early decrease in NAA concentrations was observed after only a few weeks of neurotoxic treatment, without any sign of ongoing cell death. This early decrease in striatal NAA was partially reversed after 4 weeks of 3NP withdrawal. These results demonstrate that early NAA depletions reflect a reversible state of neuronal dysfunction preceding cell degeneration and suggest that in vivo quantification of NAA 1H-magnetic resonance spectroscopy may become a valuable tool for assessing early neuronal dysfunction and the effects of potential neuroprotective therapies in neurodegenerative disorders.
Dautry
C
C
URA CEA CNRS 2210, Service Hospitalier Frédéric Joliot, Orsay, France.
Vaufrey
F
F
Brouillet
E
E
Bizat
N
N
Henry
P G
PG
Condé
F
F
Bloch
G
G
Hantraye
P
P
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000172:deficiency; D015415:Biomarkers; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009574:Nitro Compounds; D010215:Papio; D011422:Propionates / Q000506:poisoning*; D011522:Protons; D051381:Rats; D011917:Rats, Inbred Lew; D013385:Succinate Dehydrogenase / Q000378:metabolism
D015415:Biomarkers; D009574:Nitro Compounds; D011422:Propionates; D011522:Protons; D001224:Aspartic Acid; C000179:N-acetylaspartate; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid