Metal chelators as part of a strategy for the treatment of neurodegenerative diseases

Most neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and prion diseases, present similarities in the aggregation of specific proteins in the central nervous system. All these proteins have been shown to interact with metal ions with redox activity, which is fundamental in the mechanisms of neurodegeneration. Metal chelation therapy can be very important for complexing accumulated metal ions at the brain level, thus decreasing the neurotoxicity induced by them. However, so far, no metal chelator has been approved for the treatment of neurodegenerative diseases. Obstacles to their use are the adverse effects of the removal of essential metal ions from the brain as well as their low blood-brain barrier permeability. Clioquinol (PBT1) and its derivatives reduce metal aggregates in the brain, effectively crossing the blood-brain barrier, chelating metal ions, and inhibiting 13-amyloid deposition. Drugs that target a single mechanism are not sufficient to treat neurodegenerative diseases. Therefore, to be useful, a combination of drugs must have different properties, such as controlling the formation of reactive oxygen species, metal chelation capacity and increased permeability of the blood-brain barrier, decreased 13-amyloid peptide deposition, and the regulation of enzymes associated with the disease mechanism. The incorporation of a safe and effective metal chelator in the therapeutic regimen can al low for a reduction of the effective dose of the drug and complement its actions.