Redox-based therapeutics in neurodegenerative disease

Abstract

This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research.

Linked articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

Figure 1

Schematic diagram of redox‐based therapeutic strategies in neurodegenerative disease models. Arg, L‐arginine; ASSNAC, S‐allyl‐mercapto‐N‐acetyl cysteine; GSSG, oxidised glutathione; DMF, dimethylfumarate; mtNOS, mitochondrial nitric oxide synthase; resp.chain, mitochondrial respiratory chain; SAS, sulfasalazine; x_c ⁻, cystine‐glutamate exchanger.

Figure 2

A, chemical structures of low MW thiols that increase cysteine or GSH and B, compounds that target the x_c ⁻ cystine glutamate exchanger.

Figure 3

Chemical structures of various Nrf2 inducers.

Figure 4

Selected NOX inhibitors.