Quantifiable bradykinesia, gait abnormalities and Huntington's disease-like striatal lesions in rats chronically treated with 3-nitropropionic acid.
Impairment in energy metabolism is thought to be involved in the aetiology of Huntington's disease. In line with this hypothesis, chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid to rats and monkeys produces selective striatal lesions similar to Huntington's disease. The present study examined whether rats treated with varying regimen of 3-nitropropionic acid could present motor abnormalities reminiscent of Huntington's disease symptomatology, correlated with Huntington's disease specific striatal symptomatology. Subacute 3-nitropropionic acid treatment (15 mg/kg per day intraperitoneally for 10 days) produced dramatic motor symptoms associated with extensive neuronal loss and gliosis in the lateral striatum as well as severe hippocampal degeneration in 50% of the cases. In contrast, chronic 3-nitropropionic acid treatment (10 mg/kg per day subcutaneously for one month) led to more subtle excitotoxic-like lesions, selective for the dorsolateral striatum and more closely resembling Huntington's disease striatal pathology. Animals with these Huntington's disease-like lesions showed spontaneous motor symptoms including mild dystonia, bradykinesia and gait abnormalities, which were barely detectable on visual inspection but could be readily identified and quantified by computerized video analysis. In these chronic animals, the degree of striatal neuronal loss was significantly correlated with the severity of spontaneous motor abnormalities, as is the case in Huntington's disease. The present study demonstrates that chronic low-dose 3-nitropropionic acid treatment in rats results in a valuable model of both the histological features and motor deficits which occur in Huntington's disease. Despite the interanimal variability in terms of response to 3-nitropropionic acid treatment, this rat model may be particularly useful for evaluating the functional benefits of new therapeutic strategies for Huntington's disease, particularly those aiming to reduce the severity of motor symptoms.
Guyot
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MC
Service Hospitalier Frédéric Joliot, Unité de Recherche Associée 2210,Commissariat a l'Energie Atomique-Centre National de Recherche Scientifique, Département de Recherche Médicale, Orsay, France.
Hantraye
P
P
Dolan
R
R
Palfi
S
S
Maziére
M
M
Brouillet
E
E
D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D008058:Dihydrolipoamide Dehydrogenase / Q000032:analysis; D004334:Drug Administration Schedule; D005684:Gait / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D000882:Haplorhini; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D008058:Dihydrolipoamide Dehydrogenase; C015392:3-nitropropionic acid