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 co...

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Bibliographic Details
Published in:	Neurotoxicology (Park Forest South) Vol. 90; pp. 10 - 18
Main Authors:	Marwah, Praneet Kaur, Paik, Gijong, Issa, Christopher J., Jemison, Christopher C., Qureshi, Muhammad B., Hanna, Tareq M., Palomino, Eduardo, Maddipati, Krishna Rao, Njus, David
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-05-2022 Elsevier BV
Subjects:	Basal ganglia Chronic exposure Copper Cycles Dopamine Dopathiazine Ganglia Humans Hydrogen peroxide Manganese Manganese Poisoning Manganism Movement disorders Neurodegenerative diseases Oxidation-Reduction Oxidative stress Parkinson Disease Parkinson's disease Redox cycling Redox properties Selectivity Signs and symptoms NQO1 Oxidative stress Dopamine Redox cycling dopathiazine DHBT-1 Hepes SOD DTZ-2 Manganism EDTA 3MAQ Manganese Dopathiazine
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Summary:	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. [Display omitted] •DTZ-2 represents a novel class of dopamine derivatives: dopathiazines.•Redox cycling of DTZ-2 is enhanced by Mn at micromolar concentrations.•Mn accelerates the reaction of reduced DTZ-2 with O2 to form H2O2.•Reduced dopathiazines probably form a coordination complex with Mn.•Dopathiazines may account for the selective neurological effects of chronic manganese exposure.
ISSN:	0161-813X 1872-9711
DOI:	10.1016/j.neuro.2022.02.007