Brain infarct volume after permanent focal ischemia is not dependent on Nox2 expression

Kim, Hyun Ah; Brait, Vanessa H; Lee, Seyoung; Silva, T. Michael De; Diep, Henry; Eisenhardt, Anja; Drummond, Grant Raymond; Sobey, Christopher G.

doi:10.1016/j.brainres.2012.09.023

Cited by 21 publications

(28 citation statements)

References 26 publications

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“…These reports establish the significant effect of Nox4 activity on ischaemic stroke outcome in the absence of reperfusion [16,181], which is in contrast to the recent report on genetic Nox2 inhibition [168]. The protection afforded during permanent ischaemia was less than that provided during temporary ischaemia in Nox4 deficient mice [16], however these results also appear contradictory to in vitro studies showing NADPH oxidase-derived ROS were important primarily during reperfusion after OGD [25,26,27].…”

Section: Nadph Oxidase Expression and Activity After Strokesupporting

confidence: 58%

“…The reasons for this lack of concurrence are unclear but may involve methodological particularities or differences in the genetics of the specific Nox2 mouse colonies used. Nox2 deficient mice were also recently shown to lack protection following permanent ischaemia [168]. This finding suggests that reperfusion is critical for the Nox2 oxidase to play a role in ischaemic brain injury.…”

Section: Nadph Oxidase Expression and Activity After Strokementioning

confidence: 99%

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NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

McCann

Roulston

2013

Brain Sciences

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Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

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Section: Nadph Oxidase Expression and Activity After Strokesupporting

confidence: 58%

Section: Nadph Oxidase Expression and Activity After Strokementioning

confidence: 99%

NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

McCann

Roulston

2013

Brain Sciences

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“…Impaired blood flow prevents removal of accumulated H + , and reperfusion clears accumulated H + . The present findings suggest that this pH-normalizing effect of reperfusion may explain, in part, why superoxide production is greater in reperfused than nonreperfused ischemic brain, and why both NOX2 inhibitors and NMDA receptor antagonists are better neuroprotective agents in reperfused brain than nonreperfused brain (41)(42)(43). The degree of intracellular acidification shown here to influence neuronal superoxide production is within the range induced by physiological brain activity (28,44).…”

Section: +mentioning

confidence: 56%

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

Lam

Brennan-Minnella

Won

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidase generates intracellular H + along with extracellular superoxide, and the intracellular H + must be released or neutralized to permit continued NADPH oxidase function. In cultured neurons, NMDAinduced superoxide production and neuronal death were prevented by intracellular acidification by as little as 0.2 pH units, induced by either lowered medium pH or by inhibiting Na + /H + exchange. In mouse brain, superoxide production induced by NMDA injections or ischemia-reperfusion was likewise prevented by inhibiting Na + /H + exchange and by reduced expression of the Na + /H + exchanger-1 (NHE1). Neuronal intracellular pH and neuronal Na + /H + exchange are thus potent regulators of excitotoxic superoxide production. These findings identify a mechanism by which cell metabolism can influence coupling between NMDA receptor activation and superoxide production.any metabolic processes generate hydrogen ions, and hydrogen ions in turn influence cell metabolism and survival (1). Cerebral ischemia in particular produces acidosis of variable degree, depending upon blood glucose levels, degree of blood flow reduction, and other factors. Severe acidosis, below pH 6.4, exacerbates ischemic injury (2) by mechanisms involving protein denaturation, acid-sensing calcium channels, and release of ferrous iron (3-5). Conversely, lesser degrees of acidosis, in the range of 7.0-6.5, reduce both ischemic injury (6) and glutamateinduced neuronal death (7). These neuroprotective effects have been attributed to an inhibitory effect of hydrogen ions on NMDA receptor activation (8-10), but a causal link has not been demonstrated.Excessive activation of N-methyl-D-aspartate (NMDA) type glutamate receptors leads to excitotoxic cell death in stroke and other neurological disorders (11,12). Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic cell death (13)(14)(15)(16)(17)(18)(19) Together, the pH sensitivity of NOX2 and the role of NOX2 in NMDA receptor-mediated cell death suggest the possibility that reduced intracellular pH might limit neurotoxicity by dissociating NMDA receptor activation from superoxide production. Findings presented here confirm that both the superoxide production and cell death resulting from neuronal NMDA receptor activation are highly pH sensitive. We show that neurons use Na + /H + exchange as a major route of proton efflux during NOX2 activation, and either genetic or pharmacologic inhibition of neuronal Na + /H + exchange prevent both excitotoxic superoxide production and cell death. ResultsMild Acidosis Blocks NMDA-Induced Superoxide Production and Cell Death. We first performed cell culture studies at a physiological medium pH ...

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“…For instance, a majority of studies have reported that NOX2 knockout animals have significantly reduced infarct size following focal cerebral ischemia [131, 153, 157–160], although there are a few dissenting studies [140, 161]. NOX2 knockout animals also have been demonstrated to have reduced ROS and oxidative stress in the brain after focal cerebral ischemia [131, 159], as well as reduced blood brain barrier disruption [158], and significantly attenuated post-ischemic inflammation [131, 157].…”

Section: Introductionmentioning

confidence: 99%

NADPH oxidase in brain injury and neurodegenerative disorders

Merry

Wang

Zhang

et al. 2017

Mol Neurodegeneration

342

309

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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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Brain infarct volume after permanent focal ischemia is not dependent on Nox2 expression

Cited by 21 publications

References 26 publications

NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

NADPH oxidase in brain injury and neurodegenerative disorders

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