NADPH oxidases as therapeutic targets in ischemic stroke

Kahles, Timo; Brandes, Ralf P.

doi:10.1007/s00018-012-1011-8

Cited by 117 publications

(67 citation statements)

References 204 publications

(239 reference statements)

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“…Specific, small molecule inhibitors of NOX2 and other NOX isoforms are currently under development (92), and there is growing enthusiasm for using this approach in the treatment of acute stroke (24,83,147). This enthusiasm must be tempered, however, by the experience gained from prior FIG.…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Brennan-Minnella

Won

Swanson

2015

Antioxidants & Redox Signaling

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Significance: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. Recent Advances: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase f/d, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. Critical Issues: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. Future Directions: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. Antioxid. Redox Signal. 22,[161][162][163][164][165][166][167][168][169][170][171][172][173][174]

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Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Brennan-Minnella

Won

Swanson

2015

Antioxidants & Redox Signaling

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“…Ischemia or Ang II induced Nox2 protein in these cells, whereas endothelial Nox4 protein expression increased in cerebral ECs after stroke or in response to angiogenesis (Table 1) [reviewed by (88)]. …”

Section: Nox Function In the Brainmentioning

confidence: 99%

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

Kahles

Brandes²

2013

Antioxidants & Redox Signaling

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108

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Significance and Recent Advances: Ischemic stroke is the leading cause of disability and third in mortality in industrialized nations. Immediate restoration of cerebral blood flow is crucial to salvage brain tissue, but only few patients are eligible for recanalization therapy. Thus, the need for alternative neuroprotective strategies is huge, and antioxidant interventions have long been studied in this context. Reactive oxygen species (ROS) physiologically serve as signaling molecules, but excessive amounts of ROS, as generated during ischemia/ reperfusion (I/R), contribute to tissue injury. Critical Issues: Nevertheless and despite a strong rational of ROS being a pharmacological target, all antioxidant interventions failed to improve functional outcome in human clinical trials. Antioxidants may interfere with physiological functions of ROS or do not reach the crucial target structures of ROS-induced injury effectively. Future Directions: Thus, a potentially more promising approach is the inhibition of the source of disease-promoting ROS. Within recent years, NADPH oxidases (Nox) of the Nox family have been identified as mediators of neuronal pathology. As, however, several Nox homologs are expressed in neuronal tissue, and as many of the pharmacological inhibitors employed are rather unspecific, the concept of Nox as mediators of brain damage is far from being settled. In this review, we will discuss the contribution of Nox homologs to I/R injury at large as well as to neuronal damage in particular. We will illustrate that the current data provide evidence for Nox2 as the most important NADPH oxidase mediating cerebral injury.

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“…The release and impaired reuptake of endogenous glutamate during brain ischemia-reperfusion activates NMDA receptors, and the resulting production of superoxide by neuronal NOX2 is a primary cause of ischemic neuronal death (30)(31)(32)(33)(34). Therefore, we also compared superoxide formation after ischemia-reperfusion in wild-type and NHE1 +/− mouse hippocampus.…”

Section: E-h)mentioning

confidence: 99%

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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NADPH oxidases as therapeutic targets in ischemic stroke

Cited by 117 publications

References 204 publications

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Which NADPH Oxidase Isoform Is Relevant for Ischemic Stroke? The Case for Nox 2

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

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