Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease

Abstract

Many neurodegenerative disorders involve the accumulation of multimeric assemblies and amyloid derived from misfolded conformers of constitutively expressed proteins. In addition, the brains of patients and experimental animals afflicted with prion disease display evidence of heightened oxidative stress and damage, as well as disturbances to transition metal homeostasis. Utilising a variety of disease model paradigms, many laboratories have demonstrated that copper can act as a cofactor in the antioxidant activity displayed by the prion protein while manganese has been implicated in the generation and stabilisation of disease-associated conformers. This and other evidence has led several groups to test dietary and chelation therapy-based regimens to manipulate brain metal concentrations in attempts to influence the progression of prion disease in experimental mice. Results have been inconsistent. This review examines published data on transition metal dyshomeostasis, free radical generation and subsequent oxidative damage in the pathogenesis of prion disease. It also comments on the efficacy of trialed therapeutics chosen to combat such deleterious changes.

Oxidative Stress and Huntington’s Disease: The Good, The Bad, and The Ugly

“…Their chemical nature enables some transitional metals (eg. Fe, Cu, Zn) to take part in a number of physiological redox reactions [ 62 ]. A growing number of studies suggest metal dyshomeostasis may be a part of HD pathogenesis [ 63 ].…”

“…Iron is classically believed to mediate oxidative damage via Fenton chemistry [ 62 ], although more recent studies suggest that iron may permit toxicity via its ability to activate iron containing proteins such as the hypoxia inducible factor prolyl hydroxylases (HIF PHDs) [ 69 ]. By contrast, copper has been shown to directly interact with N-terminal end of huntingtin to catalyze cysteine oxidation, cross-linking at its N-terminal end and consequent mHtt oligomerization.…”

Silicon Oxynitrophosphide Nanoscale Coating Enhances Antioxidant Marker‐Induced Angiogenesis During in vivo Cranial Bone‐Defect Healing

“…One step is the cation is reduced as it reduces superoxide. The other step involves the oxidation of the cation as superoxide is reduced (82) . This means that the cation acts as a catalyst and as such conserves charge.…”

“…The other step involves the oxidation of the cation as superoxide is reduced. ( 82 ) This means that the cation acts as a catalyst and as such conserves charge. For Si, the increased valence state of Si undergoes more moles of superoxide reduction.…”

“…Antioxidant metalo-enzymes are activated by transition metal cations such as Cu 2+ , Zn 2+ , and Mg 2+ because of their ability to present electrons in a third orbital state for reaction with the enzymes. (81,82) This is required to overcome the spin orbital restriction associated with enzyme activity for this family of enzymes. (83) We have shown in prior work that SiONx and SiONPx induce spin orbit splitting in which 2p Si electrons transition to third theoretical orbitals when N is added to their structures.…”