Intravenous HOE-642 Reduces Brain Edema and Na Uptake in the Rat Permanent Middle Cerebral Artery Occlusion Model of Stroke: Evidence for Participation of the Blood–Brain Barrier Na/H Exchanger

O’Donnell, Martha E; Chen, Yi‐Je; Lam, Tina I.; Taylor, Kelleen C; Walton, Jeffrey H.; Anderson, Steven E.

doi:10.1038/jcbfm.2012.160

Cited by 63 publications

(70 citation statements)

References 38 publications

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“…In ischemic stroke, brain edema formation is one of the most important pathologic processes [131], in which VP exerts a pivotal role [132,133]. VP release and expression of its receptors in the brain increase significantly following ischemia, trauma or subarachnoid hemorrhage in patients and in animal models of these diseases [134].…”

Section: Clinically Relevant Studiesmentioning

confidence: 99%

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

Hou¹,

Feng²,

Li³

et al. 2016

Biochem Pharmacol (Los Angel)

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Section: Clinically Relevant Studiesmentioning

confidence: 99%

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

Hou¹,

Feng²,

Li³

et al. 2016

Biochem Pharmacol (Los Angel)

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“…The structure of HOE predicts that it does not cross an intact blood-brain barrier (40), necessitating delivery by stereotactic injection in the studies of its effect on acute excitotoxicity in vivo. Homozygous NHE1 −/− mice cannot be used because they have seizures, spontaneous mortality, and compensatory changes in gene expression (29); however, NHE1 +/− mice provide a useful complement to the HOE studies because these mice have reduced NHE1 activity.…”

Section: +mentioning

confidence: 99%

“…It should be noted, however, that NHE1 deficiency has additional effects that can influence outcome from brain ischemia. Reduced sodium accumulation in NHE1 +/− neurons may promote neuronal survival (29), and reduced sodium accumulation in nonneuronal cells limits brain edema (40). Moreover, suppression of NOX2 activation by NHE1 or Hv1 inhibition in microglia inhibits the innate immune response, and may thereby promote neuronal survival in the postischemic interval (21)(22)(23).…”

Section: +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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“…13–18 During the early hours of ischemic stroke, cerebral edema forms in the presence of an intact BBB as transendothelial secretion of Na + , Cl − and water into the brain is greatly increased. 10–12, 17, 18 Previous studies have provided evidence that this involves ischemia stimulation of luminal NKCC and NHE activity and that inhibition of these transporters by intravenously administered bumetanide or HOE642 effectively reduces edema and brain Na + uptake 17 . The primary anion accompanying Na + in ischemia-induced BBB secretion is Cl − .…”

Section: Introductionmentioning

confidence: 99%

Blood–Brain Barrier KCa3.1 Channels

Chen

Wallace

Yuen

et al. 2015

Stroke

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Background and Purpose KCa3.1, a calcium-activated potassium channel, regulates ion and fluid secretion in the lung and gastrointestinal tract. It is also expressed on vascular endothelium where it participates in blood pressure regulation. However, the expression and physiological role of KCa3.1 in blood-brain barrier (BBB) endothelium has not been investigated. BBB endothelial cells transport Na+ and Cl− from the blood into the brain transcellularly through the cooperation of multiple co-transporters, exchangers, pumps and channels. In the early stages of cerebral ischemia, when the BBB is intact, edema formation occurs by processes involving increased BBB transcellular Na+ transport. This study evaluated whether KCa3.1 is expressed on and participates in BBB ion transport. Methods The expression of KCa3.1 on cultured cerebral microvascular endothelial cells (CMEC), isolated microvessels and brain sections was evaluated by Western blot and immunohistochemistry. Activity of KCa3.1 on CMEC was examined by K+ flux assays and patch-clamp. Magnetic resonance spectroscopy and imaging were used to measure brain Na+ uptake and edema formation in rats with focal ischemic stroke following TRAM-34 treatment. Results KCa3.1 current and channel protein were identified on bovine CMEC and freshly isolated rat microvessels. In situ KCa3.1 expression on BBB endothelium was confirmed in rat and human brain sections. TRAM-34 treatment significantly reduced Na+ uptake, and cytotoxic edema in the ischemic brain. Conclusions BBB endothelial cells exhibit KCa3.1 protein and activity and pharmacological blockade of KCa3.1 appears to provide an effective therapeutic approach for reducing cerebral edema formation in the first 3 hours of ischemic stroke.

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Intravenous HOE-642 Reduces Brain Edema and Na Uptake in the Rat Permanent Middle Cerebral Artery Occlusion Model of Stroke: Evidence for Participation of the Blood–Brain Barrier Na/H Exchanger

Cited by 63 publications

References 38 publications

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

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

Blood–Brain Barrier KCa3.1 Channels

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