RÉSUMÉ
In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson's disease (PD), dopaminergic (DA) neurons have been shown to die by apoptosis. Moreover, recent postmortem and in vitro results have indicated that apoptotic cell death induced by 1-methyl-4-phenylpyridinium (MPP(+)) may be mediated by caspase-3. To establish whether caspase-3 activation may indeed play a role in an in vivo model of PD, we studied caspase-3 activation in C57Bl/6 mice subchronically intoxicated with MPTP. We show that caspase-3 activation peaks early, at days 1 and 2 after the end of MPTP intoxication. In contrast, pycnotic neurons persist until day 7 postintoxication, indicating that caspase-3 activation is an early and transient phenomenon in apoptotic death of DA neurons. We further demonstrate that loss of tyrosine hydroxylase (TH) immunoreactivity in this model is indeed due to cell loss rather than to loss of TH protein expression. We conclude that mice subchronically intoxicated with MPTP represent a valid PD model to study and manipulate caspase activation in vivo.
Sujet(s)
1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine/effets indésirables , Caspases/métabolisme , Modèles animaux de maladie humaine , Agents dopaminergiques/effets indésirables , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine/administration et posologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Caspase-3 , Agents dopaminergiques/administration et posologie , Immunohistochimie , Mâle , Souris , Souris de lignée C57BL , Neurones/effets des médicaments et des substances chimiques , Neurones/enzymologie , Neurones/anatomopathologie , Syndrome parkinsonien secondaire/induit chimiquement , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/enzymologie , Tyrosine 3-monooxygenase/métabolismeRÉSUMÉ
Caspase-3 is an effector of apoptosis in experimental models of Parkinson's disease (PD). However, its potential role in the human pathology remains to be demonstrated. Using caspase-3 immunohistochemistry on the postmortem human brain, we observed a positive correlation between the degree of neuronal loss in dopaminergic (DA) cell groups affected in the mesencephalon of PD patients and the percentage of caspase-3-positive neurons in these cell groups in control subjects and a significant decrease of caspase-3-positive pigmented neurons in the substantia nigra pars compacta of PD patients compared with controls that also could be observed in an animal model of PD. This suggests that neurons expressing caspase-3 are more sensitive to the pathological process than those that do not express the protein. In addition, using an antibody raised against activated caspase-3, the percentage of active caspase-3-positive neurons among DA neurons was significantly higher in PD patients than in controls. Finally, electron microscopy analysis in the human brain and in vitro data suggest that caspase-3 activation precedes and is not a consequence of apoptotic cell death in PD.