Inhibition by anion channel blockers of ischemia-evoked release of excitotoxic and other amino acids from rat cerebral cortex

Phillis, John W.; Song, Dekun; O’Regan, Michael H.

doi:10.1016/s0006-8993(97)00155-8

Cited by 104 publications

(67 citation statements)

References 37 publications

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“…VRACs probably play a major role in mediating excessive EAA release during cerebral ischemia (3)(4)(5)(6). The potent VRAC blocker tamoxifen reduces infarct size after transient and global ischemia, although the exact mechanism of tamoxifen protection remains to be elucidated (79,80).…”

Section: Discussionmentioning

confidence: 99%

“…Volume-regulated anion channels (VRACs) are thought to constitute a major pathway for EAA release, as suggested by the inhibition of pathological glutamate and aspartate release by several VRAC blockers in animal models of global and focal cerebral ischemia (3)(4)(5)(6). VRACs are ubiquitously expressed, activated in response to cell swelling, and characterized by Eisenman type I anion selectivity (I Ϫ Ͼ NO 3 Ϫ Ͼ Br Ϫ Ͼ Cl Ϫ Ͼ F Ϫ ), moderate outward rectification, and inactivation at positive potentials (7)(8)(9).…”

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confidence: 99%

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Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Haskew-Layton

Mongin

Kimelberg³

2005

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Haskew-Layton

Mongin

Kimelberg³

2005

Journal of Biological Chemistry

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“…In the rat global ischemia model, using a cortical cup technique, Phillis et al found 30-70% inhibition of glutamate and aspartate release with the anion channel blockers 2 mM 4-acetamido-4'-isothiocyanostrilbene-2,2'-disulfonic acid (SITS), 350 μM NPPB, 200 μM dipyridamole, or 20 μM tamoxifen [65,66]. In a microdialysis study, also done in the global ischemia model, Seki et al found that another anion channel inhibitor 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS) reduced ischemic release of excitotoxins by 50-70% , when added at 1 or 10 mM in microdialysis perfusate [67].…”

Section: Volume-regulated Anion Channels and The Reversed Mode Of Glumentioning

confidence: 99%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

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“…VRACs may be a major contributor to neuronal damage in ischemia (Kimelberg, 2000;Kimelberg, 2005;Phillis et al, 1997;Ochoa De La Paz LD et al, 2002;Law, 1991). Excess EAAs, primarily extracellular glutamate, initiate a cascade of events progressing over hours to many days (Lipton, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Excess EAAs, primarily extracellular glutamate, initiate a cascade of events progressing over hours to many days (Lipton, 1999). The increase in extracellular EAAs may occur through a number of routes, including exacerbation by decreased reuptake into neurons and astrocytes, exocytotic release from neurons, reversal of the high affinity uptake system and swelling-induced opening of anion channels, especially in astrocytes (Nicholls and Attwell, 1990;Kimelberg and Mongin, 1998;Mongin and Kimelberg, 2004;Law, 1994;Quesada et al, 1998;Pasantes-Morales et al, 1990;Phillis et al, 1997;Phillis et al, 2000;Strange et al, 1994;Liu et al, 2006). Prevention or inhibition of ischemia-induced EAA release, either acute or prolonged, may protect neurons in 'at risk' locations.…”

Section: Introductionmentioning

confidence: 99%

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Zhang

Feustel

et al. 2008

Experimental Neurology

113

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Previous studies have indicated that volume regulated anion channels (VRACs) may be involved in the pathology of the ischemic brain cortical penumbra due to activation of VRAC-mediated excitatory amino-acid (EAA) release. To assess this we had studied neuroprotection and EAA release inhibition by a potent VRAC inhibitor, tamoxifen. However, tamoxifen inhibits several other neurodamaging processes. In the present study we use an ethacrynic acid derivative, 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), that has recently been shown to be a specific antagonist of volume regulated anion channels (VRAC), to measure the extent of neuroprotection provided and thus to better assess the role of VRAC-mediated release of excitatory amino acids in an intraluminal suture, reversible middle cerebral artery occlusion (rMCAO) model in adult rats. Rats given DCPIB intracisternally had significantly better neurobehavioral scores after 24 hours and showed significantly reduced infarct volumes. Mean infarct volumes were 208.0 (SD = 38.3) mm 3 for the vehicle groups, compared with 68.5 (SD = 22.7) mm 3 for intracisternally DCPIBtreated groups (p=0.02, Mann-Whitney test), a reduction of around 75%. However, a 500-fold higher dose of DCPIB given intravenously did not reduce infarct volume or improve behavior. The microdialysis study demonstrated statistically significant reduced brain extracellular fluid glutamate when DCPIB was present in the probe. Thus DCPIB, a specific inhibitor of VRACs, given i.c. provides strong neuroprotection in brain ischemia, but it appears to not cross the blood brain barrier as it is not effective when given i.v. These experiments support the hypothesis that EAA released via VRACs contributes to later ischemic-induced damage.

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Inhibition by anion channel blockers of ischemia-evoked release of excitotoxic and other amino acids from rat cerebral cortex

Cited by 104 publications

References 37 publications

Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

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