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Cited by 433Redox biology and oxidative stressNitric Oxide and Endothelin EffectsNeutrophil, Myeloperoxidase and Oxidative Mechanisms

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NADPH oxidase in brain injury and neurodegenerative disorders

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Ma, Merry W., Wang, Jing, Zhang, Quanguang, Wang, Ruimin, Dhandapani, Krishnan M., Vadlamudi, Ratna K., Brann, Darrell W.·2017·Molecular Neurodegeneration
DOI 10.1186/s13024-017-0150-7PMC PMC5240251
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Abstract

Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.

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Fig. 1 a Cellular Sources of ROS. ROS can be generated intracellularly via the action of various organelles, enzymes, and processes. b Conversion of Superoxide to Secondary ROS. Once produced, superoxide can interact with various molecules to generate secondary radicals. Superoxide can react with nitric oxide to produce peroxynitrite. Superoxide dismutase can also convert superoxide into hydrogen peroxide, which can then undergo a Fenton reaction to produce hydroxyl radicals and ions. Interaction of superoxide with protons can produce hydroperoxyl radicals. These secondary radicals are highly reactive and can be neurotoxic via alterations of macromolecules and amplification of oxidative stress
Fig. 1 a Cellular Sources of ROS. ROS can be generated intracellularly via the action of various organelles, enzymes, and processes. b Conversion of Superoxide to Secondary ROS. Once produced, superoxide can interact with various molecules to generate secondary radicals. Superoxide can react with nitric oxide to produce peroxynitrite. Superoxide dismutase can also convert superoxide into hydrogen peroxide, which can then undergo a Fenton reaction to produce hydroxyl radicals and ions. Interaction of superoxide with protons can produce hydroperoxyl radicals. These secondary radicals are highly reactive and can be neurotoxic via alterations of macromolecules and amplification of oxidative stressCC BY · PubMed Central
Fig. 2 NOX isoforms and regulatory subunits. NADPH oxidases have a primary role to generate ROS. Several components and domains make up the transmembrane active enzyme complexes of NADPH oxidase isoforms. NOX1-5 and DUOX1/DUOX2 are shown here. Upon activation, an electron will be transferred from NADPH to O2 to form superoxide. NOX4 generated superoxide undergoes rapid conversion into hydrogen peroxide, which mediates many of its downstream effects. NOX5 and the DUOX enzymes are sensitive to cellular Ca2+ concentrations
Fig. 2 NOX isoforms and regulatory subunits. NADPH oxidases have a primary role to generate ROS. Several components and domains make up the transmembrane active enzyme complexes of NADPH oxidase isoforms. NOX1-5 and DUOX1/DUOX2 are shown here. Upon activation, an electron will be transferred from NADPH to O2 to form superoxide. NOX4 generated superoxide undergoes rapid conversion into hydrogen peroxide, which mediates many of its downstream effects. NOX5 and the DUOX enzymes are sensitive to cellular Ca2+ concentrationsCC BY · PubMed Central

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Authors
Ma, M. W., Wang, J., Zhang, Q., Wang, R., Dhandapani, K. M., Vadlamudi, R. K., & Brann, D. W.
Affiliations
  • Augusta University (US)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Brann, Darrell W.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2017-01-17
Volume
12
Issue
1
Pages
7-7
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-017-0150-7
PMC
PMC5240251
OpenAlex
W2574254633
Cited by
432
References
417
Citations by year
2026: 21 · 2025: 45 · 2024: 43 · 2023: 59 · 2022: 44 · 2021: 67 · 2020: 49 · 2019: 38 · 2018: 40 · 2017: 26
FWCI
3.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (5l101BX001117)
  • National Institute of Neurological Disorders and Stroke (5R01NS050730, R01NS088058)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
NADPH oxidase, oxidative stress, neurodegenerative diseases, brain injury, ischemic brain injury, traumatic brain injury, NOX1, NOX2, NOX4, neuroprotection, antioxidant therapy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis
MeSH terms
Animals, Brain Injuries, Humans, NADPH Oxidases, Neurodegenerative Diseases

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