Removal of Toxic Metabolites-Chelation: Manganese Disorders

Manganese (Mn) overload is a characteristic of multiple disease entities, from acquired manganism upon environmental or occupational overexposure, to end-stage liver disease and certain genetic disorders. The latter include hypermanganesaemia with dystonia 1 and 2 caused by pathogenic variants in the genes encoding the Mn transporters SLC30A10 and SLC39A14. Excess Mn accumulates in the brain, particularly in the globus pallidus, leading to progressive dystonia-parkinsonism. Furthermore, Mn dyshomeostasis is a characteristic feature of common neurodegenerative disorders such as Parkinson's disease, whether as a cause or consequence needs to be determined, suggesting that Mn as an environmental toxicant may play a role in its aetiology. Therefore, there is a need for therapeutics that effectively chelate Mn and remove excess Mn from the brain. This review discusses the Mn chelators currently used in clinical practice, their advantages and disadvantages as well as their adverse effects. Na₂CaEDTA is the primary chelating agent used to re-establish Mn homeostasis; however, its burdensome treatment regimen, need for intravenous administration, and lack of metal specificity make it a poor drug for clinical application. The development of novel, Mn-specific chelating agents is therefore a clinical priority. An ideal chelator would be orally bioavailable, soluble in both lipids and water to reach the sites of metal storage, chemically inert, and non-toxic whilst retaining chelating abilities at physiological pH. We discuss current progress in identifying novel Mn ligands that have been primarily developed as magnetic resonance imaging contrast agents.