Oxidation Chemistry of Dopamine: Possible Insights into the Age-Dependent Loss of Dopaminergic Nigrostriatal Neurons

The oxidation chemistry of the chemical neurotransmitter dopamine (DA) has been investigated using electrochemical approaches. At physiological pH in aqueous solution DA is initially oxidized at a pyrolytic graphite electrode in a reversible 2e, 2H+ reaction to give DA-o-quinone (1). Deprotonation and intramolecular cyclization of 1 yields 5,6-dihydroxyin-doline (3) which is rapidly further oxidized (2e, 2H+) to 6-hydroxyindoline-6-one (4; dopaminochrome). Compound 4 then rearranges to 5,6-dihydroxyindole (5) which for the first time has been unequivocally identified as an oxidation product of DA. When preconcentrated on a preparative reversed-phase HPLC column 5 undergoes an unusual nonoxidative dimerization reaction to give 2-(5 ,6-dihydroxyindoline-3-yl)-5,6-dihydroxyindole (7). This 2,3′-linked indole-indoline dimer is extremely toxic when centrally administered to laboratory mice and evokes complex behavioral responses including convulsions, tremor, and hyperactivity. DA is known to undergo autoxidation in the cytoplasm of dopaminergic substantia nigra neurons to give neuromelanin polymer. Based on the results obtained in this study it is speculated that 5, a necessary intermediate in the latter reaction, is adsorbed on neuromelanin and reacts to form 7 which along with DA-o-quinone (1) and dopaminochrome (4) might be endotoxins that contribute to the age-dependent degeneration of dopaminergic SN neurons. In the presence of L-cysteine DA-o-quinone (1) reacts to give 5-S-cysteinyldopamine (8) not 6-S-cysteinyldopamine as has been suggested by other investigators.