In vivo models of multiple system atrophy

Pierre-Olivier Fernagut, Imad Ghorayeb, Elsa Diguet, François Tison
Movement Disorders. 2005-01-01; 20(S12): S57-S63
DOI: 10.1002/mds.20541

1. Mov Disord. 2005 Aug;20 Suppl 12:S57-63. doi: 10.1002/mds.20541.

In vivo models of multiple system atrophy.

Fernagut PO(1), Ghorayeb I, Diguet E, Tison F.

Author information:
(1)Department of Neurology, University of California Los Angeles, USA.

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative
disorder of unknown etiology clinically characterized by a combination of
parkinsonian, pyramidal, and cerebellar signs. Levodopa-unresponsive
parkinsonism is present in 80% of MSA cases, and this dominant clinical
presentation (MSA-P) is associated with a combined degeneration of the
substantia nigra pars compacta and the striatum in anatomically related areas.
The limited knowledge of the pathophysiology of MSA and the lack of therapeutic
strategies prompted the development of lesion models reproducing striatonigral
degeneration, the substrate of levodopa-unresponsive parkinsonism in MSA-P. This
method was carried out first in rats with two different stereotaxic strategies
using either two neurotoxins (« double toxin-double lesion ») or a single
neurotoxin (« single toxin-double lesion »). Double-lesioned rat models showed
severe motor impairment compared to those with a single nigral or striatal
lesion and helped to mimic different stages of the disease. Systemic models were
also developed in mice and primates using the nigral toxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the striatal toxin
3-nitropropionic (3-NP). In mice, although MPTP reduced the subsequent
sensitivity to 3-NP in a sequential lesion, simultaneous nigral and striatal
insults were shown to exacerbate striatal damage. MPTP-treated monkeys displayed
a significant worsening of parkinsonism and a loss of levodopa-responsiveness
after the appearance of hindlimb dystonia and striatal lesion formation induced
by subsequent 3-NP intoxication. The different species and intoxication
paradigms used will be useful to investigate functional changes in substantia
nigra and striatum and to define neuroprotective, neurorestorative, or
symptomatic therapeutic strategies.