Strategy to reduce free radical species in Alzheimer’s disease: an update of selected antioxidants

Abstract

Alzheimer’s disease (AD), characterized by progressive loss of memory, language, reasoning and other cognitive functions, including dementia, is characterized pathologically by the presence of senile plaques, neurofibrillary tangles and synapse loss. Increased oxidative/nitrosative stress, decreased antioxidants, mitochondrial damage and other factors play major roles in the development and progression of AD. Strategies to reduce pro-oxidant species to ameliorate AD pathology have been proposed with mixed results. In this review, we focus on the most recent in vitro and in vivo antioxidant approaches for removing oxidant species with relevance to AD, including N-acetyl-l-cysteine, vitamin D, vitamin E, ferulic acid, tricyclodecan-9-yl-xanthogenate, selenium and melatonin as therapeutic stratagems in AD management. In addition, we reviewed the most effective mitochondria targeted antioxidants such as coenzyme Q10 and lipoic acid. We suggest the use of multitargeted approaches by formulas containing one or more antioxidant compounds may be more promising than single-agent approaches.

Keywords:

• Alzheimer’s disease
• antioxidants
• dementia
• free radicals
• neurodegenerative

Financial & competing interests disclosure

This work was supported by NIH grant AG-05119 to DA Butterfield and funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° 624341 to E Barone. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Oxidative/nitrosative stress (OS) has a major role in the pathogenesis of Alzheimer’s disease (AD) leading to the damage of vital cellular components such as proteins, lipids and nucleic acids.

• Compounds with antioxidant activity have been proposed for prevention of cognitive decline and treatment of AD and its early stages.

• N-Acetyl-l-cysteine showed protection against pro-oxidant species and amyloid β-peptide (Aβ) toxicity though the increase of glutathione levels in animal models and humans.

• Tricyclodecan-9-yl-xanthogenate was able to reduce reactive oxygen species, protein oxidation and glutathione/glutathione disulfide ratio in ex vivo studies.

• Selenium supplementation in AD animal models and patients demonstrated promising effects in recovering endogenous antioxidants and reducing Aβ production.

• Vitamin E is able to lower lipid peroxidation and β-amyloid deposition; however, its efficacy might be related to the redox status of the patient.

• Ferulic acid protects biological membranes from lipid peroxidation and neutralized peroxyl and alkoxyl radicals and is a modulator of β-secretase activity in vitro and in vivo.

• Chronic low dietary-derived vitamin D levels in the bloodstream are associated with increased protein tyrosine nitration, alterations in glucose metabolism and mitochondrial changes in the brain.

• N-Acetyl-l-cysteine, selenium and vitamin E are currently used in ongoing multitargeted clinical trials in combination with other drugs with the rationale to ameliorate OS-induced AD pathology.

• Melatonin reduced OS only in in vitro and in vivo animal models by reducing Aβ levels and τ phosphorylation, but failed to improve AD-associated symptoms when administered to humans.

• Mitochondria being both source and objective of reactive oxygen species represent a valuable therapeutic target; supplementation with mitochondria-focused antioxidants, such as coenzyme Q10 or lipoic acid alone or in formulas, is currently of high interest.