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 ARTICLESThis 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 Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

Alpha-Lipoic Acid improves the testicular dysfunction in rats induced by varicocele

“…Antioxidant therapy is one of the most promising therapeutic strategies for neurodegenerative and skin diseases (McBean, Lopez, & Wallner, ) and has been also considered for treatment of infertility (Calogero, Condorelli, Russo, & La Vignera, ). Treatment of male infertility by oral antioxidants such as vitamins A, C and E, carnitine, folate, zinc and selenium decreases level of oxidative stress and improves sperm parameter after three or six months (Garg & Kumar, ; Showell et al, ).…”

Salidroside Protects against MPP+-Induced Neuronal Injury through DJ-1-Nrf2 Antioxidant Pathway

“…PD is attributed to loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and characterized by the presence of ubiquitinated alpha-synuclein- ( α -syn-) containing cytoplasmic inclusions called Lewy bodies in surviving SNpc neurons [3, 4]. Although the accurate mechanism of PD is not known, oxidative injury and associated apoptotic cell death are believed to play an important role [2, 5, 6]. Large quantity of studies has shown that antioxidant intervention is effective for the treatment of PD and other neurodegenerative diseases [6].…”

Evaluation of the Antioxidant Activity of the Marine Pyrroloiminoquinone Makaluvamines

“…Therefore, the Nrf2 pathway has been extensively studied and its role in neurodegenerative diseases has been confirmed. The protective effect of Nrf2 activation has led to the development of a FDA approved drug, Tecfidera (dimethyl fumarate), Biogen Idec (Cambridge, MA, USA), for the treatment of patients with relapsing multiple sclerosis and the application of Nrf2 activators for other diseases is currently being researched [28,29,30]. The development of new antioxidant molecules that have effects on mitochondria and on the antioxidant enzymes can contribute to the expansion of our knowledge about the potential of antioxidant therapies in neurodegenerative diseases.…”