NOX5 as a therapeutic target in cerebral ischemic injury

Carmo, Luciana S; Berk, Bradford C.; Harrison, David G.

doi:10.1172/jci127682

Cited by 12 publications

(4 citation statements)

References 10 publications

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“…However, NOX4 preferentially generates H 2 O 2 rather than O 2 − [ 34 ]. Accumulating evidence also shows that under condition of ischemia/reperfusion (I/R), increased levels of intracellular Ca 2+ result in activation of NOX5 and subsequently increases the production of O 2 − , OONO − , and H 2 O 2 , leading to the disruption of the BBB [ 35 , 36 ]. Consistently, levels of ROS were increased following I/R injury in hippocampal brain slices from NOX-5 knock-in mice [ 36 ].…”

Section: Oxidative Stress In Multiple Cells That Constitute or Surrou...mentioning

confidence: 99%

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

et al. 2022

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The blood–brain barrier (BBB), which consists mainly of brain microvascular endothelial cells and astrocytes connected by tight junctions (TJs) and adhesion molecules (AMs), maintains the homeostatic balance between brain parenchyma and extracellular fluid. Accumulating evidence shows that BBB dysfunction is a common feature of neurodegenerative diseases, including stroke, traumatic brain injury, and Alzheimer’s disease. Among the various pathological pathways of BBB dysfunction, reactive oxygen species (ROS) are known to play a key role in inducing BBB disruption mediated via TJ modification, AM induction, cytoskeletal reorganization, and matrix metalloproteinase activation. Thus, antioxidants have been suggested to exert beneficial effects on BBB dysfunction-associated brain diseases. In this review, we summarized the sources of ROS production in multiple cells that constitute or surround the BBB, such as BBB endothelial cells, astrocytes, microglia, and neutrophils. We also reviewed various pathological mechanisms by which BBB disruption is caused by ROS in these cells. Finally, we summarized the effects of various natural polyphenols on BBB dysfunction to suggest a therapeutic strategy for BBB disruption-related brain diseases.

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Section: Oxidative Stress In Multiple Cells That Constitute or Surrou...mentioning

confidence: 99%

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

et al. 2022

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“…Alterations in the BBB integrity can lead to several pathologic events, such as the leakage of plasma proteins, the infiltration of immune cells, the activation of microglial cells and localized and increased cytokine production. These could be associated with the increased cerebral infarct size in the NOX5-expressing mice, performed by Casas et al [ 49 ]. Therefore, NOX5 may participate in neuronal degeneration mediated by BBB alterations triggered via ROS accumulation that allow to postulate this oxidase as a therapeutic target in cerebral ischemic injury.…”

Section: Discussionmentioning

confidence: 99%

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

et al. 2021

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Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.

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“…Besides, further studies should be performed in order to obtain specific inhibitors for this oxidase. In this regard, it is the first and only crystallized NADPH oxidase and there are relevant studies suggesting that NOX5 could be a good therapeutic target in vascular diseases as diabetic nephropathy [ 59 , 67 , 87 ], cerebral ischemic injury [ 18 ], acute myocardial infarction or stroke [ 77 ], as well as in some types of cancer [ 9 ] and a potential target of cancer cell sensitivity to chemotherapies, such as cisplatin [ 32 , 61 ]. Lastly, future works would be needed to explore the epigenetic regulation of the NOX5 gene and the posttranslational regulation of the protein which are still unknown so far, and the interaction with other proteins that affects its activity.…”

Section: Role Of Nox5 In Physiology and Pathophysiologymentioning

confidence: 99%

Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5)

et al. 2023

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NOX5 is the last member of the NADPH oxidase (NOXs) family to be identified and presents some specific characteristics differing from the rest of the NOXs. It contains four Ca2+ binding domains at the N-terminus and its activity is regulated by the intracellular concentration of Ca2+. NOX5 generates superoxide (O2•−) using NADPH as a substrate, and it modulates functions related to processes in which reactive oxygen species (ROS) are involved. Those functions appear to be detrimental or beneficial depending on the level of ROS produced. For example, the increase in NOX5 activity is related to the development of various oxidative stress-related pathologies such as cancer, cardiovascular, and renal diseases. In this context, pancreatic expression of NOX5 can negatively alter insulin action in high-fat diet-fed transgenic mice. This is consistent with the idea that the expression of NOX5 tends to increase in response to a stimulus or a stressful situation, generally causing a worsening of the pathology. On the other hand, it has also been suggested that it might have a positive role in preparing the body for metabolic stress, for example, by inducing a protective adipose tissue adaptation to the excess of nutrients supplied by a high-fat diet. In this line, its endothelial overexpression can delay lipid accumulation and insulin resistance development in obese transgenic mice by inducing the secretion of IL-6 followed by the expression of thermogenic and lipolytic genes. However, as NOX5 gene is not present in rodents and human NOX5 protein has not been crystallized, its function is still poorly characterized and further extensive research is required.

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NOX5 as a therapeutic target in cerebral ischemic injury

Cited by 12 publications

References 10 publications

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

Effects of Natural Polyphenols on Oxidative Stress-Mediated Blood-Brain Barrier Dysfunction

Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

Structure, regulation, and physiological functions of NADPH oxidase 5 (NOX5)

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