Nadph Oxidase Mediates Striatal Neuronal Injury after Transient Global Cerebral Ischemia

Yoshioka, Hideyuki; Niizuma, Kuniyasu; Katsu, Masataka; Okami, Nobuya; Sakata, Hiroyuki; Kim, Gab Seok; Narasimhan, Purnima; Chan, Pak H.

doi:10.1038/jcbfm.2010.166

Cited by 90 publications

(71 citation statements)

References 40 publications

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“…Therefore, we also compared superoxide formation after ischemia-reperfusion in wild-type and NHE1 +/− mouse hippocampus. Wild-type mice showed a robust and rapid increase in superoxide production in CA1 pyramidal neurons, consistent with prior results (31,32). By contrast, NHE1 +/− mice showed no significant increase in neuronal superoxide production, as measured by either Eth or 4HNE formation (Fig.…”

Section: E-h)supporting

confidence: 80%

“…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%

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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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Section: E-h)supporting

confidence: 80%

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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“…Bilateral injuries to the striatum were in particular more frequent than those to the hippocampal CA1 subregion, another vulnerable brain region. Although striatal injury after tGCI has not received much attention, some authors have also reported that striatal neurons are the most vulnerable in C57BL/6 mouse brains after tGCI (Gillingwater et al, 2004;Olsson et al, 2003;Terashima et al, 1998;Yang et al, 1997;Yoshioka et al, 2010). Therefore, a striatal injury model that uses C57BL/6 mice can be appropriate for studying neuronal death after tGCI.…”

Section: Discussionmentioning

confidence: 99%

“…Aspiny interneurons, the remaining 5%, can be categorized into medium GABAergic interneurons and large cholinergic interneurons (Kreitzer, 2009). Although MSNs are reported to be the most vulnerable to tGCI of the striatal neurons (Terashima et al, 1998;Yoshioka et al, 2010), quantitative evaluation of their vulnerability has not been studied.…”

Section: Introductionmentioning

confidence: 99%

Consistent Injury to Medium Spiny Neurons and White Matter in the Mouse Striatum after Prolonged Transient Global Cerebral Ischemia

Yoshioka

Niizuma

Katsu

et al. 2011

Journal of Neurotrauma

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A reproducible transient global cerebral ischemia (tGCI) mouse model has not been fully established. Although striatal neurons and white matter are recognized to be vulnerable to ischemia, their injury after tGCI in mice has not been elucidated. The purpose of this study was to evaluate injuries to striatal neurons and white matter after tGCI in C57BL/6 mice, and to develop a reproducible tGCI model. Male C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion (BCCAO). Mice whose cortical cerebral blood flow after BCCAO decreased to less than 13% of the pre-ischemic value were used. Histological analysis showed that at 3 days after 22 min of BCCAO, striatal neurons were injured more consistently than those in other brain regions. Quantitative analysis of cytochrome c release into the cytosol and DNA fragmentation in the striatum showed consistent injury to the striatum. Immunohistochemistry and Western blot analysis revealed that DARPP-32-positive medium spiny neurons, the majority of striatal neurons, were the most vulnerable among the striatal neuronal subpopulations. The striatum (especially medium spiny neurons) was susceptible to oxidative stress after tGCI, which is probably one of the mechanisms of vulnerability. SMI-32 immunostaining showed that white matter in the striatum was also consistently injured 3 days after 22 min of BCCAO. We thus suggest that this is a tGCI model using C57BL/6 mice that consistently produces neuronal and white matter injury in the striatum by a simple technique. This model can be highly applicable for elucidating molecular mechanisms in the brain after global ischemia.

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“…Ischemiareperfusion increases the NOX2 activity in the brain, and both inhibitors of NOX2 activity and genetic downregulation or deficiency of NOX2 components reduce oxidative stress and infarct size in focal cerebral ischemia (81,89,90,178,186). These manipulations likewise reduce oxidative stress and neuronal death after transient forebrain ischemia (77,172,193,195 phox -/ -neurons, which cannot assemble a functional NOX2 complex, were transfected at low efficiency with GFP-labeled p47 phox (green) to reconstitute the NOX2 activity in a small fraction of cultured neurons. The cultures were treated with 100 lM Nmethyl-D-aspartate (NMDA) for 30 min.…”

Section: Fig 1 Nadph Oxidase (Nox)mentioning

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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Nadph Oxidase Mediates Striatal Neuronal Injury after Transient Global Cerebral Ischemia

Cited by 90 publications

References 40 publications

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

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

Consistent Injury to Medium Spiny Neurons and White Matter in the Mouse Striatum after Prolonged Transient Global Cerebral Ischemia

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

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