CHEMICAL EVIDENCE FOR 6-HYDROXYDOPAMINE TO BE AN ENDOGENOUS TOXIC FACTOR IN THE PATHOGENESIS OF PARKINSONS-DISEASE

The presence of 5-Hydroxydopamine (5-OHDA) and 6-Hydroxydopamine (6-OH DA) in the urine of parkinsonian patients on levodopa medication was r eported by Andrew et al. (1993). To answer the question about the puta tive relevance of 6-OHDA endogenously formed in the brain for the path ogenesis of Parkinson's disease (PD), the chemical mechanisms leading to dopamine-coordinative complexes were investigated in vitro. Kinetic studies of the reaction of dopamine (DA) with dioxygen over the pH ra nge 7.0-9.0, where it reacts spontaneously without the necessity of me tal-ion analysis, show that stoichiometric amounts of H2O2 are produce d. Pink dopaminochrome, another oxidation product, is not stable and f urther reacts - without the consumption of dioxygen - to form the inso luble polymeric material known as melanin. Based on these results, the in vitro chemistry of the reactions of DA, 5-OHDA, and 6-OHDA in the presence of Fe3+ and dioxygen are studied. A mechanism for the initiat ion of a chain reaction is suggested by which excess Fe3+ could arise, and its relevance for the degeneration of dopaminergic neurons in PD is discussed. Detailed studies on the release of ferritin bound iron ( 0.2-1.4 mu M Fe3+) by synthetic DA (200 mu M) may provide further insi ght into the pathogenesis of PD,but further studies are warranted to e lucidate the molecular basis of this neurodegenerative disorder of the extrapyramidal system.