MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration

P.O. Fernagut, E. Diguet, B. Bioulac, F. Tison
Experimental Neurology. 2004-01-01; 185(1): 47-62
DOI: 10.1016/j.expneurol.2003.09.014

1. Exp Neurol. 2004 Jan;185(1):47-62. doi: 10.1016/j.expneurol.2003.09.014.

MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice:
reference to striatonigral degeneration.

Fernagut PO(1), Diguet E, Bioulac B, Tison F.

Author information:
(1)Physiologie et Physiopathologie de la Signalisation Cellulaire, UMR-CNRS
5543, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex, France.

Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined
degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc)
and striatal output neurons. The aims of this study were to explore (1) the
behavioral and histopathological consequences of combined MPTP plus
3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to
reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p.
every 12 h (total dose=450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day)
(total dose=90 mg/kg in 9 days). Four groups of mice (n=10) were compared:
control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and
MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping,
truncal dystonia and impaired balance adjustments. The severity of motor
disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to
3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also
displayed altered gait patterns, impaired motor performance on the pole test,
rotarod and traversing a beam tasks and activity parameters. Several of these
sensorimotor deficits were also more severe and lasted longer in MPTP +
3-NP-treated mice. Histology demonstrated increased neuronal loss along with
astrocytic activation (glial fibrillary acid protein, GFAP) and a higher
incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice
compared to 3-NP. Neuronal loss and astrocytic activation were increased in the
lateral part of the striatum in 3-NP-intoxicated mice while observed both in the
medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a
significant loss of SNc dopaminergic neurons and striatal terminals, similar to
that in MPTP-treated mice. Altogether, these results suggest that MPTP
potentiates striatal damage and behavioral impairments induced by 3-NP
intoxication in mice and constitutes a useful model of the motor disorder and
its histopathological correlates in SND.