Strategies for the protection of dopaminergic neurons against neurotoxicity.

Abstract

Degenerative diseases of the central nervous system (CNS) frequently have a predilection for specific cell populations. An explanation for the selective vulnerability of particular neuronal populations and the mechanisms of cell death remains, as yet, elusive. Partial elucidation of the processes underlying the selective action of neurotoxic substances such as iron, 6-hydroxydopamine (6-OHDA), glutamate, kainic acid, quinolinic acid or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has revealed possible molecular mechanisms for neurodegeneration. Hypotheses regarding the neurotoxic mechanisms of these substances have evolved based on our understanding of the pathogenesis of cell death in neurodegenerative disorders and have been the rationale for neuroprotective approaches. Various experimental models have demonstrated that monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists exert a neuroprotective effect at the cellular, neurochemical and functional levels, however as yet it has not been possible to demonstrate an unequivocal neuroprotective effect of these substances in clinical studies. This does not suggest, however, that the pathogenetic processes underlying neurodegenerative disorders are not amenable to neuroprotective treatment. This chapter briefly reviews the mechanisms underlying dopaminergic cell death in Parkinson's disease (PD) as an example of a neurodegenerative disorder and discusses preclinical approaches which attempt to demonstrate the neuroprotective effects of representative drugs in experimental models of this disorder. The problems associated with carrying out clinical neuroprotective studies aimed to demonstrate neuroprotection in PD are also discussed.