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

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 proces ses such as oxidative stress and mitochondrial inhibition are largely descr ibed. However, despite these findings, the actual therapeutics are essentia lly symptomatical and are not able to block the degenerative process. Recen t histological studies performed on brains from PD patients suggest that ni gral cell death could be apoptotic. However. since post-mortem studies do n ot allow precise determination of the sequence of events leading to this ap optotic cell death, the molecular pathways involved in this process have be en essentially studied on experimental models reproducing the human disease . These latter are created by using neurotoxic compounds such as 6-hydroxyd opamine (6-OHDA), 1-methyl-1-4-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 characteris tics 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 underly ing the experimental models of PD and correlates them to the phenomena occu rring in human disease. (C) 2001 Elsevier Science Ltd. All rights reserved.