Adenosine-stimulated astroglial swelling in cat cerebral cortex in vivo with total inhibition by a non-diuretic acylaryloxyacid derivative

Rs, Bourke; Jb, Waldman; Hk, Kimelberg; Kd, Barron; Bd, San Filippo; Aj, Popp; Lr, Nelson

doi:10.3171/jns.1981.55.3.0364

Cited by 36 publications

(17 citation statements)

References 33 publications

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“…DCPIB displays minimal inhibition of other Cl − and K + currents (< 10% inhibition at 10 µM), and inhibits glucose-stimulated insulin secretion in intact β-cells via VRAC inhibition and indirect K ATP channel activation. It reverses cell swelling-induced action potential duration shortening in atrial myocytes and inhibits astroglial swelling in vitro (Abdullaev et al, 2006;Bourke et al, 1981;Best et al, 2004). DCPIB has been shown to be a specific antagonist of volume regulated anion channels (VRAC) using cell expression systems where it was shown not to have any effect on a variety of expressed Cl − channels , but to be a very effective inhibitor of VRAC activity in swollen cells (Decher et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Synthesis of these compounds was guided by the principle of increasing their efficacy in inhibiting brain edema and reducing their renal saludiuretic effects (Nelson et al, 1979;Kimelberg et al, 1987;Kimelberg et al, 1990;Bourke et al, 1979;Cragoe et al, 1982;Cragoe, Jr. et al, 1986;Cragoe, 1987). Since that time one of these compounds 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid and therefore given the acronym DCPIB Bourke et al, 1981;Nelson et al, 1982); and see Figure 1a), has been shown to specifically inhibit VRAC activity, but not a number of expressed chloride channels in Xenopus oocytes (Decher et al, 2001). VRACs are an important class of anion channels that are widely distributed, but whose molecular identity has so far eluded investigators' best efforts (Nilius and Droogmans, 2003;Strange, 1998;Okada, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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

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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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Section: Discussionmentioning

confidence: 99%

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

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113

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“…To verify the specificity of DCPIB action we analysed the effect of ethacrynic acid (EA), the molecule from which DCPIB is derived (Bourke et al, 1981;Cragoe et al, 1982). In COS-7 cells transfected with K2P 2.1 and K2P 10.1 that responded to DCPIB (10 mM) application of 30 mM EA did not cause any increase in membrane conductance ( Figure 5C, D).…”

Section: Figurementioning

confidence: 99%

“…One of the best characterized agent that modulates these processes is the ethacrynic acid derivative, 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxobutyric acid (DCPIB). DCPIB was reported to block totally astroglial swelling induced in cat cerebral cortex (Bourke et al, 1981). In adult rats, DCPIB caused a reduction in size of infarct volume when applied intracisternally during 2 h of middle cerebral artery occlusion (MCAO), and decreased MCAO-induced glutamate release in the penumbra (Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The inhibitor of volume‐regulated anion channels DCPIB activates TREK potassium channels in cultured astrocytes

Minieri

Pivoňková

Caprini

et al. 2013

British J Pharmacology

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Background and PurposeThe ethacrynic acid derivative, 4‐(2‐butyl‐6,7‐dichlor‐2‐cyclopentylindan‐1‐on‐5‐yl) oxobutyric acid (DCPIB) is considered to be a specific and potent inhibitor of volume‐regulated anion channels (VRACs). In the CNS, DCPIB was shown to be neuroprotective through mechanisms principally associated to its action on VRACs. We hypothesized that DCPIB could also regulate the activity of other astroglial channels involved in cell volume homeostasis.Experimental ApproachExperiments were performed in rat cortical astrocytes in primary culture and in hippocampal astrocytes in situ. The effect of DCPIB was evaluated by patch‐clamp electrophysiology and immunocytochemical techniques. Results were verified by comparative analysis with recombinant channels expressed in COS‐7 cells.Key ResultsIn cultured astrocytes, DCPIB promoted the activation of a K+ conductance mediated by two‐pore‐domain K+ (K2P) channels. The DCPIB effect occluded that of arachidonic acid, which activates K2P channels K2P 2.1 (TREK‐1) and K2P 10.1 (TREK‐2) in cultured astrocytes. Immunocytochemical analysis suggests that cultured astrocytes express K2P 2.1 and K2P 10.1 proteins. Moreover, DCPIB opened recombinant K2P 2.1 and K2P 10.1 expressed in heterologous system. In brain slices, DCPIB did not augment the large background K+ conductance in hippocampal astrocytes, but caused an increment in basal K+ current of neurons.Conclusion and ImplicationsOur results indicate that the neuroprotective effect of DCPIB could be due, at least in part, to activation of TREK channels. DCPIB could be used as template to build new pharmacological tools able to increase background K+ conductance in astroglia and neuronal cells.

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“…The increase in taurine release by adenosine may occur to compensate the osmotic imbalance triggered by adenosine-induced astroglial swelling via cAMP accumulation (Bourke et al, 1981). It is not clear why and how adenosine causes astroglial swelling.…”

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Activation of adenosine A2 receptors enhances high K+-evoked taurine release from rat hippocampus: A microdialysis study

et al. 1998

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The present study was designed to examine which type of adenosine receptors was involved in enhancement of high K(+)-evoked taurine release from in vivo rat hippocampus using microdialysis. Perfusion with 0.5 or 5.0 mM adenosine enhanced high K(+)-evoked taurine release. Perfusion with 2 microM R(-)-N6-2-phenylisopropyladenosine (PIA), a selective adenosine A1 receptor agonist, did not modulate taurine release. Perfusion with 1 microM 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, increased taurine release. On the other hand, perfusion with 20 microM 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamide-adenos ine (CGS21680), a selective adenosine A2A receptor agonist, enhanced taurine release, while perfusion with 1 mM 3,7-dimethyl-propagylxanthine (DMPX), an adenosine A2 receptor antagonist, did not affect taurine release. These results demonstrate that adenosine enhances high K(+)-evoked taurine release via activation of adenosine A2A receptors from both neurons and glial cells of in vivo rat hippocampus.

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Adenosine-stimulated astroglial swelling in cat cerebral cortex in vivo with total inhibition by a non-diuretic acylaryloxyacid derivative

Cited by 36 publications

References 33 publications

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

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

The inhibitor of volume‐regulated anion channels DCPIB activates TREK potassium channels in cultured astrocytes

Activation of adenosine A2 receptors enhances high K+-evoked taurine release from rat hippocampus: A microdialysis study

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