Manganese-stimulated redox cycling of dopamine derivatives: Implications for manganism

Manganism, the condition caused by chronic exposure to high levels of manganese, selectively targets the dopamine-rich basal ganglia causing a movement disorder with symptoms similar to Parkinson's disease. While the basis for this specific targeting is unknown, we hypothesize that it may involve complexation of Mn by dopamine derivatives. At micromolar concentrations, MnCl₂ accelerates the two-equivalent redox cycling of a dopamine-derived benzothiazine (dopathiazine) by an order of magnitude. In the process, O₂ is reduced to superoxide and hydrogen peroxide. This effect is unique to Mn and is not shared by Fe, Cu, Zn, Co, Ca or Mg. Notably, the effect of Mn requires the presence of inorganic phosphate, suggesting that phosphate may stabilize a Mn/catecholate complex, which reacts readily with O₂. This or similar endogenous dopamine derivatives may exacerbate Mn-dependent oxidative stress accounting for the neurological selectivity of manganism.