Early increase of Nox4 NADPH oxidase and superoxide generation following endothelin‐1‐induced stroke in conscious rats

McCann, Sarah; Dusting, Gregory J.; Roulston, Carli L

doi:10.1002/jnr.21700

Cited by 69 publications

(76 citation statements)

References 38 publications

(56 reference statements)

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“…24,25 As identified by OX42 immunoreactivity in the current study, there was an increase in the number of activated microglia after stroke, as previously reported using this same stroke model. 26 Moreover, there was also an obvious change in microglia appearance from an amoeboid shape to a phenotype exhibiting processes, when moving from the infarcted core to peri-infarct region (see Figure 5); a finding that has also been demonstrated in different models of stroke in rats and is indicative of phagocytosis of cellular debris. 27,28 Strikingly, AT 2 R stimulation after stroke was associated with a significant elevation in the number of activated microglia in the core region of the infarct at 3 days after stroke.…”

Section: 23mentioning

confidence: 62%

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

McCarthy

Vinh²,

Broughton³

et al. 2012

Hypertension

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A ngiotensin II (Ang II) can bind to several receptor subtypes, thus, influencing an array of cardiovascular functions in the body. However, the 2 major receptor subtypes are the angiotensin II type 1 receptor (AT 1 R), which is thought to be responsible for most of the biological and pathological actions of Ang II, and the angiotensin II type 2 receptor (AT 2 R), which mainly opposes the actions of the AT 1 R.1 Several largescale clinical trials 2,3 have indicated that the use of AT 1 R antagonists as a method of blood pressure control in high-risk patients improves cardiac and vascular events, which results in a reduced risk of secondary events such as stroke. This is consistent with experimental studies reporting that central or peripheral pretreatment with an AT 1 R antagonist reduces postischemic inflammation and the size of the cerebral infarction together with improved behavioral symptoms. [4][5][6][7][8] Importantly, neuroprotection has been demonstrated to occur even with nonhypotensive doses of AT 1 R blockers. 9 The postulated nonvascular mechanisms of neuroprotection include inhibition of neuronal apoptosis 5 and reduced neuronal loss associated with inhibition of superoxide production and inflammation, 10 although there is likely to be a contribution from the AT 2 R during AT 1 R blockade.6,7 Indeed, several groups have reversed neuroprotection induced during AT 1 R blockade with the coadministration of an AT 2 R antagonist, suggesting that the AT 2 R is a pivotal component in the therapeutic action of AT 1 R antagonists. 6,7 In addition, mice lacking the AT 2 R show poorer outcome after stroke and are less receptive to the protective influence of AT 1 R antagonists.11,12 Thus, there is accumulating indirect evidence that suggests that the AT 2 R may have a cerebroprotective role during stroke, although little is known about direct AT 2 R stimulation in the brain.In this context, we have recently examined the neuroprotective effect of direct AT 2 R stimulation after intracerebroventricular (ICV) administration of the AT 2 R agonist CGP42112 in a conscious rat model of stroke. Our results indicate that, even in the absence of AT 1 R blockade, direct stimulation of the central AT 2 R for 5 days before and for 3 days after stroke dramatically reduces subsequent damage, both histologically and behaviorally, such that at 72 hours after stroke injury is minimal. 13 Given that patients normally present for treatment after a cerebrovascular event, a clinically relevant treatment needs to be effective when administered after a stroke has occurred. To this end, the current proof-of-principle study investigated the potential neuroprotective role of See Editorial Commentary, pp 1391-1392Abstract-We have demonstrated previously that pretreatment with an angiotensin II type 2 receptor (AT 2 R) agonist is neuroprotective against a subsequent stroke independent of any changes in blood pressure. Therefore, in the current study, we have examined the potential neuroprotective effect of AT 2 R stimulation initiated aft...

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Section: 23mentioning

confidence: 62%

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

McCarthy

Vinh²,

Broughton³

et al. 2012

Hypertension

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“…Ischemic stroke is a leading cause of death (171), and the repeated failure of promising experimental stroke treatments in human clinical trials (127) makes it likely that this situation will not change soon. Both NOX2 and NOX4 have been implicated in stroke pathogenesis (128,140,182). Most animal studies have used the transient middle cerebral artery occlusion model, measuring infarct volume and blood-brain barrier permeability as parameters that increase after occlusion and reperfusion.…”

Section: Ischemic Conditionsmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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“…Also, Nox4 expression changes in stroke models: Nox4 mRNA increased early after ET-1 induced stroke in the cortex of rats (112) and in neurons and in newly formed capillaries surrounding the ischemic core (167). Also in vessels, a dramatic induction of Nox4 occurs after stroke (118).…”

Section: Nox Expression In the Course Of Cerebral I/rmentioning

confidence: 99%

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

Kahles

Brandes²

2013

Antioxidants & Redox Signaling

109

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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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Early increase of Nox4 NADPH oxidase and superoxide generation following endothelin‐1‐induced stroke in conscious rats

Cited by 69 publications

References 38 publications

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

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

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