Reorganizing Metals: the Use of Chelating Compounds as Potential Therapies for Metal-Related Neurodegenerative Disease

Abstract

Metal ions, particularly copper, zinc and iron, are implicated in several amyloidogenic neurodegenerative disorders. In the brain, as elsewhere in the body, metal ion excess or deficiency can potentially inhibit protein function, interfere with correct protein folding or, in the case of iron or copper, promote oxidative stress. The involvement of metal ions in neurodegenerative disorders has made them an emerging target for therapeutic interventions. One approach has been to chelate and sequester the ions and thus limit their potential to interfere with protein folding or render them unable to undergo redox processes. Newer approaches suggest that redistributing metal ions has therapeutic benefits, and recent studies indicate that alleviating cellular copper deficiency may be a plausible way to limit neurodegeneration. In this review we discuss the role of metals in amyloidogenic, neurodegenerative disorders and highlight some mechanisms and compounds used in various therapeutic approaches.

Bioinorganic Chemistry of Alzheimer’s Disease

“…860−863 In addition to being antioxidant and metal-chelating with the optimal K d and selectivity between targeted metal ions, these compounds should also be hydrophobic and capable of crossing the BBB and must be of reasonable small molecular weight and fulfill various other, typical criteria of druglikeness. 445,864,865 Here, six such candidates will be discussed: lipoic acid, N-acetyl-L-cysteine (NAC), epigallocatechin gallate (EGCG), curcumin, melatonin, and galantamine. 863,866 Lipoic acid is a coenzyme for pyruvate dehydrogenase in the mitochondria and thus plays a role in neuronal energy production.…”

The iron regulatory capability of the major protein participants in prevalent neurodegenerative disorders

“…Instrumental work carried out on therapeutic design in the body’s periphery (Higgs et al, 2012; Zhou et al, 2012) has increasingly been implemented to investigate their value at restoring iron homeostasis within the brain (Zecca et al, 2004; Badrick and Jones, 2011; Zorzi et al, 2012). However, a significant hurdle in the use of these drugs has been the relative impermeability to the blood brain barrier for some of the more effective peripheral tissue therapeutics and the necessity to target iron in brain rather than the periphery.…”

Chelation Therapy for Iron Overload

“…1,2,11,16,18–20 Another possible avenue for research is the development of formulas that have modified bioavailability, such as slow-release formulation, or compounds that combine iron chelation with antioxidant properties. 5,11 …”