Elsevier

Progress in Neurobiology

Volume 65, Issue 2, October 2001, Pages 135-172
Progress in Neurobiology

Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease

https://doi.org/10.1016/S0301-0082(01)00003-XGet rights and content

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease.

Introduction

Parkinson's disease (PD) is a widespread neurodegenerative disorder. Even though the neurochemical defects and the neuropathological characteristics of this disease are well defined, its etiology is still unknown. Additionally, given the current absence of neuroprotective therapies, its treatment remains symptomatic. New advances in molecular neuroscience recently led to the idea that neuronal degeneration may be stopped and that specific neuroprotective strategies could be possible. However, this step will only be attained if the molecular pathways of neuronal cell death involved in PD are better understood. The determination of molecular mechanisms of neuronal death in human brain encounters methodological and biological problems. Therefore, in-vivo and in-vitro models using experimental neurotoxins are essential since they allow the study of degenerating processes as well as new therapeutic approaches.

In this review, we present the recent advances in the knowledge of the molecular mechanisms underlying PD and the contribution of experimental models to this field.

Section snippets

Parkinson's disease

Parkinson's disease, first described by James Parkinson in 1817 (Parkinson, 1817), is a neurodegenerative disorder that can be defined as a syndrome associated with specific neuropathological lesions.

General observations

6-Hydroxydopamine is one of the most common neurotoxins used to experimentally model nigral degeneration in vitro as well as in vivo. 6-OHDA is a hydroxylated analogue of the natural dopamine neurotransmitter. It was originally isolated by Senoh in 1959 (Senoh and Witkop, 1959a, Senoh and Witkop, 1959b, Senoh et al., 1959a, Senoh et al., 1959b). Its biological effects were first demonstrated by Porter et al., 1963, Porter et al., 1965 and Stone et al. (1963), who showed that 6-OHDA induces

Relevance of experimental data for human nigral degeneration

All the data presented here strongly suggest that experimental in-vitro and in-vivo models of PD may help to determine which factors could be critical in the molecular pathways leading to degeneration of nigral cells. However, these results are only indicative and need post-mortem confirmation to estimate the real occurrence of such processes. Only a small amount of data are available to date, probably due to the complexity of obtaining and interpreting results obtained in human samples (see

Conclusion

Throughout this review, we have presented evidence suggesting that experimental models reproduce the main cellular modifications occurring in PD. 6-OHDA, DA and MPTP are able to induce two of the main biochemical defects in PD, namely oxidative stress and mitochondrial inhibitions as well as histological lesions. Other aspects of the human disease are, however, not reproduced (Hantraye, 1998): the precise anatomical lesion, the time course of the disease (decades vs. weeks at best), the

Acknowledgements

This work was supported by INSERM, Université Joseph Fourier and MESR. D.B. holds financial support from Fondation pour la Recherche Médicale (France), Fondation Simone et Cino Del Duca (France) et Fonds National pour la Recherche Scientifique (Belgium). We thank Prof. J.P. Brion, Dr M.C. Galas, Dr D. Gall, Dr P. Laduron, Dr V. Gaveau, Dr R. Hourez and Prof. S.N. Schiffmann for critical reading of the manuscript and Dr F.J. Hemming for English revision.

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