DOI 10.1007/s00702-004-0206-z J Neural Transm (2005) 112: 613–631 Effects of riluzole on combined MPTP + 3-nitropropionic acid-induced mild to moderate striatonigral degeneration in mice E. Diguet 1 , P.-O. Fernagut 1 , C. Scherfler 2 , G. Wenning 2 , and F. Tison 1 1 Physiologie et Physiopathologie de la Signalisation Cellulaire, UMR-CNRS 5543, Universit  e Victor Segalen-Bordeaux2, Bordeaux, France 2 Department of Neurology, University Hospital, Innsbruck, Austria Received March 12, 2004; accepted July 16, 2004 Published online October 22, 2004; # Springer-Verlag 2004 Summary. We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP þ 3-nitropropionic acid (3-NP) intoxication producing combined stri- atal and nigral degeneration (SND) in mice. We used a ‘‘neuronal rescue’’ strategy by administering riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and riluzole groups (10 mg=kg and 20 mg=kg), matched by triplets for motor severity. While riluzole did not produce any effect on the gross motor dis- order nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, riluzole has limited ‘‘neuronal rescue’’ properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP þ 3-NP-induced SND in mice. Keywords: Riluzole, striatonigral degeneration, MPTP, 3-nitropropionic acid, mice. Introduction ‘‘Atypical’’ parkinsonism or ‘‘Parkinson-plus’’ disorders have in common their poor prognosis and levodopa unresponsiveness. The later is due the combined degeneration of both the substantia nigra pars compacta dopami-