Human
manganese poisoning or manganism results in damage to the substantia nigra of the brain stem, a drop in the level of the inhibitory
neurotransmitter dopamine, and symptoms resembling those of
Parkinson's disease. Manganic (Mn3+)
manganese ions were shown to be readily produced by O-2 in vitro and spontaneously under conditions obtainable in the human brain. Mn3+ as its
pyrophosphate complex was shown to rapidly and efficiently carry out four-electron oxidations of
dopamine, its precursor
dopa (3,4-dihydroxyphenylalanine), and its biosynthetic products
epinephrine and
norepinephrine. Mn3+-
pyrophosphate was shown to specifically attack dihydroxybenzene derivatives, but only those with adjacent
hydroxyl groups. Further, the addition of Mn2+-
pyrophosphate to a system containing a flux of O2- and
dopamine greatly accelerated the oxidation of
dopamine. The oxidation of
dopamine by Mn3+ neither produced nor required O2, and Mn3+ was far more efficient than Mn2+, Mn4+ (MnO2), O2-, or H2O2 in oxidizing the
catecholamines. A higher oxidation state, Mn(
OH)3, formed spontaneously in an aqueous Mn(
OH)2 precipitate and slowly darkened, presumably being oxidized to MnO2. Like
reagent MnO2, it weakly catalyzed
dopamine oxidation. However, both MnO2 preparations showed dramatically increased abilities to oxidize
dopamine in the presence of
pyrophosphate due to enhancement of the spontaneous formation of the Mn3+ complex. These results strongly suggest that the pathology of
manganese neurotoxicity is dependent on the ease with which simple Mn3+ complexes are formed under physiological conditions and the efficiency with which they destroy
catecholamines.