title: Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice: behavioural and histopathological characterisation.
abstract: Data on motor behavioural disorders induced by systemic 3-nitropropionic acid, an irreversible inhibitor of mitochondrial succinate dehydrogenase and their histopathological correlates in mice, are sparse. We thus further characterised the subacute 3-nitropropionic-acid-induced motor disorder and its time course in C57Bl/6 mice using standard behavioural tests, histopathological correlates and in vivo magnetic resonance imaging. Firstly, we studied two intoxication paradigms (340 and 560 mg 3-nitropropionic acid/kg, 7 days) compared to controls. The low-dose regimen induced only slight motor changes (reduced hindlimb stride length and rearing). The high-dose regimen induced significant (P<0.05) behavioural and sensorimotor integration deficits (pole test, rotarod, stride length, open-field spontaneous activity) but with 37.5% lethality at week one. The clinical motor disorder consisted of hindlimb clasping and dystonia, truncal dystonia, bradykinesia and impaired postural control. Histopathologically, there were discrete lesions of the dorsolateral striatum in 62.5% of mice together with a 32% reduction (P<0.0001) of the striatal volume, reduced caldbindin-D28K immunoreactivity in the lateral striatum, and met-enkephalin and substance P in the striatal output pathways. There was also a significant (P<0.05) 30-40% dopaminergic cell loss within the substantia nigra pars compacta. Secondly, we validated a semi-quantitative behavioural scale to describe the time course of the motor deficits and to predict the occurrence of striatal damage. We sought to determine whether it could also be disclosed in vivo by magnetic resonance imaging. The scale correlated with the striatal volume reduction (r(2)=0.57) and striatal cell loss (r(2)=0.87) but not with the loss of striatal dopaminergic terminals (dopamine transporter binding). Increased T2-signal intensity within the striatal lesion correlated with the cell loss (r(2)=0.66). We conclude that systemic administration of 3-nitropropionic acid in C57Bl/6 mice induces a distinct motor disorder and dose-dependent striatonigral damage, which are potentially useful to model human diseases of the basal ganglia.
authors.affiliation: Laboratoire de Neurophysiologie, Physiologie et Physiopathologie de la Signalisation Cellulaire, UMR-CNRS 5543, Université Victor Segalen, Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France.
authors.forename: P O
authors.initials: PO
authors.lastname: Fernagut
authors.forename: E
authors.initials: E
authors.lastname: Diguet
authors.forename: N
authors.initials: N
authors.lastname: Stefanova
authors.forename: M
authors.initials: M
authors.lastname: Biran
authors.forename: G K
authors.initials: GK
authors.lastname: Wenning
authors.forename: P
authors.initials: P
authors.lastname: Canioni
authors.forename: B
authors.initials: B
authors.lastname: Bioulac
authors.forename: F
authors.initials: F
authors.lastname: Tison
mesh_terms: D000367:Age Factors; D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D003292:Convulsants / Q000506:poisoning*; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects*; D009574:Nitro Compounds; D011187:Posture; D011422:Propionates / Q000506:poisoning*; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology
chemical_list: D003292:Convulsants; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid