MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration P.O. Fernagut, 1 E. Diguet, 1 B. Bioulac, and F. Tison * Physiologie et Physiopathologie de la Signalisation Cellulaire, UMR-CNRS 5543, Universite ´ Victor Segalen Bordeaux2, 33076 Bordeaux cedex, France Received 6 May 2003; revised 16 September 2003; accepted 26 September 2003 Abstract 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. D 2003 Elsevier Inc. All rights reserved. Keywords: MPTP; 3-NP; Striatonigral degeneration; Motor behavior; Astrocytic activation; Mouse Introduction The substantia nigra pars compacta (SNc) dopaminergic neurons and the striatum are prone to neurodegeneration of Parkinson’s disease (PD) and Huntington’s disease (HD), respectively (Beal, 2001; Brouillet et al., 1999). They display particular sensitivity to the various forms of energy compromise that can lead to neuronal loss and secondary excitotoxic damage: the striatum is sensitive to hypoxia, ischemia or inhibition of mitochondrial complex II (Gould and Gustine, 1982); and SNc displays an almost specific sensitivity to the inhibition of mitochondrial complex I by MPTP (Nicklas et al., 1985; Scotcher et al., 1990).A unique situation of combined degeneration of the SNc and the striatum occurs in striatonigral degeneration (SND), the main clinical presentation of the sporadic adult-onset human neurodegenerative disease known as multiple sys- tem atrophy (MSA). Parkinsonism unresponsive to dopa- minergic drugs is the core feature of SND or MSA (Tison et al., 1995) and is due to such a combined degeneration with a distribution of neuronal loss roughly similar to that observed in HD and PD (Fearnley and Lees, 1990). Striatal neuronal loss affects both striatal output pathways and is assumed to be partly responsible for the dopaminergic unresponsiveness of the parkinsonian syndrome of SND or MSA (Tison et al., 1995). However, a specific cytopa- thology distributed in the cortico –subcortical motor loops is also found in this disease and consists in cytoplasmic or nuclear glial or neuronal inclusions containing alpha-syn- 0014-4886/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2003.09.014 * Corresponding author. Laboratoire de Neurophysiologie, Universite ´ Victor Segalen Bordeaux2, UMR-CNRS 5543, Bat 2a, Zone Nord, 146 rue Le ´o Saignat, 33076 Bordeaux cedex, France. Fax: +33-05-56-90-14-21. E-mail address: ftison@neuro.u-bordeaux2.fr (F. Tison). 1 These two authors contributed equally to this work. www.elsevier.com/locate/yexnr Experimental Neurology 185 (2004) 47 – 62