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Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy)

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Abstract

We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of striatonigral degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model).In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% (P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.

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Acknowledgements

The authors thank Mr. Harald Granbichler for his excellent technical assistance. This study was supported by the Austrian Science Foundation (FWF) grant P 14633-PHA.

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  1. Department of Neurology, University Hospital of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria

    Nadia Stefanova, Zoe Puschban, Pierre-Olivier Fernagut, Emmanuel Brouillet, François Tison, Markus Reindl, Kurt A. Jellinger, Werner Poewe & Gregor K. Wenning

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  1. Nadia Stefanova
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Stefanova, N., Puschban, Z., Fernagut, PO. et al. Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy). Acta Neuropathol 106, 157–166 (2003). https://doi.org/10.1007/s00401-003-0717-y

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