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Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice:
P O Fernagut1, E Diguet, N Stefanova
1Laboratoire 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.
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.
Insights
Systemic 3-nitropropionic acid in mice causes motor deficits and striatonigral damage, offering a model for basal ganglia diseases. High doses induce significant motor impairments and cell loss, correlating with imaging findings.
Area of Science:
- Neuroscience
- Toxicology
- Pathology
Background:
- Motor behavioral disorders and their histopathological correlates induced by systemic 3-nitropropionic acid (3-NPA) are not well-documented.
- 3-NPA is an irreversible inhibitor of mitochondrial succinate dehydrogenase.
Purpose of the Study:
- To characterize the subacute 3-NPA-induced motor disorder and its time course in C57Bl/6 mice.
- To investigate the histopathological correlates, including striatal and dopaminergic damage.
- To assess the utility of in vivo magnetic resonance imaging (MRI) and a behavioral scale in detecting these changes.
Main Methods:
- Two intoxication paradigms (340 and 560 mg/kg 3-NPA for 7 days) were compared to controls.
- Standard behavioral tests (pole test, rotarod, open-field activity), histopathology, and in vivo MRI were employed.
- A semi-quantitative behavioral scale was developed and validated against histopathological findings and MRI.
Main Results:
- High-dose 3-NPA induced significant motor deficits (clasping, dystonia, bradykinesia) and sensorimotor integration impairments, with 37.5% lethality.
- Histopathology revealed striatal lesions, reduced striatal volume, altered immunoreactivity, and significant dopaminergic cell loss in the substantia nigra.
- The behavioral scale correlated well with striatal volume reduction and cell loss, and increased striatal T2-signal intensity on MRI correlated with cell loss.
Conclusions:
- Systemic 3-NPA administration in C57Bl/6 mice reliably induces a distinct motor disorder and dose-dependent striatonigral damage.
- This model is potentially useful for studying human basal ganglia diseases.
- In vivo MRI and a validated behavioral scale can effectively monitor the progression and severity of the induced pathology.
