Oxidative Stress and Parkinson's Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting primarily the dopamine (DA) neurons that arise in the midbrain (mesencephalon) and project to the putamen and caudate regions (the striatum) of the brain, areas concerned with the control of motor movements (Hornykiewicz and Kish, 1986). Unaffected (or minimally affected) by the disease are DA neurons that arise in the midbrain and project to cortical and limbic regions; overactivity of the latter neuronal circuits has been implicated in schizophrenia (e.g., Lozoncy et al., 1987). Also unaffected are other monoaminergic neurons, specifically the norepinephrine (NE)-secreting and serotonin-secreting neurons of the brain. The DA neurons that degenerate in PD arise in the substantia nigra, a local region of the midbrain. As its name implies, this region is normally heavily pigmented; the pigment is readily visible to the unaided eye as a brown-to-black region of the mesencephalon. The pigment is an insoluble polymer that is related to melanin of skin, and has been termed neuromelanin. However, unlike skin, the pigment is not derived by enzymatic synthesis from L-dopa catalyzed by tyrosinase, because tyrosinase is absent from the brain. Rather, neuromelanin appears to be formed via a slow, nonenzymatic process based on the autoxidation and spontaneous polymerization of the catecholamine DA (Graham, 1978). As with melanin of skin, quinoidal intermediates react with soluble tissue thiols, such as glutathione and cysteine, to incorporate sulfur residues into the matrix of the polymer (Carstam et al., 1992).