Abstract
Manganese toxicity can evoke neuropsychiatric and neuromotor symptoms, which have frequently been attributed to profound oxidative stress in the dopaminergic system. However, the characterization of manganese as a pro-oxidant remains controversial because antioxidant properties also have been associated with this metal. The current study was designed to address these disparate findings concerning the oxidative properties of manganese. The apparent ability of manganese in its divalent form to promote formation of reactive oxygen species (ROS) within a cortical mitochondrial-synaptosomal (P2) fraction was completely abolished by the addition of one five hundredth of its molarity of desferroxamine (DFO), a trivalent metal chelator. This large ratio and the high specificity of DFO for trivalent metal ions discounted the possibility of inhibition of ROS generation by direct sequestration of divalent manganese, and implied the trace presence of a trivalent metal. Further analysis suggested that this trace metal was manganic rather than ferric ion. Ferric ion was able to dampen the reactive oxygen species-generating capacity of manganous chloride, whereas manganic ion markedly promoted this property attributed to manganous ion. Such findings of the potent effects of trace amounts of trivalent cations upon Mn 2+-related free radical generation offer resolution of earlier disparate findings concerning the oxidative character of manganese.
Highlights
Chronic exposure to manganese devastates the central nervous system with symptoms strikingly similar to schizophrenia and Parkinsonism [1,2]
The findings indicate that manganese may promote unwanted free radical reactions, the redox dynamics between its lower and higher valence states differ from that of other pro-oxidant metals
Manganous-promoted reactive oxygen species (ROS) formation quenched by chelator DFO
Summary
Chronic exposure to manganese devastates the central nervous system with symptoms strikingly similar to schizophrenia and Parkinsonism [1,2]. Brain lesions, marked by neuronal degeneration [3], are focal within brain regions that are active in oxidative metabolism and have a significant dopamine content, such as the rat hypothalamus or primate substantia nigra [4] Due to their high consumption of oxygen, these regions tend to generate large quantities of hydrogen peroxide (H2O2) and superoxide anion (O2Ϫ). The cell normally relies on transition metals to modulate and transport oxygen, the presence of free transition metals that are not bound to proteins creates the potential danger for promotion of unwanted free radical reactions Such an excess of transition metals may exert a pro-oxidant effect and initiate neuronal degeneration
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