Agents for the treatment of brain injury. 1. (Aryloxy)alkanoic acids

Cragoe, E. J.; Gould, N. P.; Woltersdorf, Otto W.; Ziegler, Carl B.; Bourke, Robert S.; Nelson, Louis R.; Kimelberg, Harold K.; Waldman, J. B.; Popp, Alfred; Sedransk, Nell

doi:10.1021/jm00347a017

Cited by 45 publications

(12 citation statements)

References 2 publications

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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%

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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Section: Figurementioning

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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“…This is good evidence that the two systems are different molecular structures. (Ary1oxy)alkanoic acids inhibit bicarbonate-induced swelling of astroglia and C1-transport by astrocytes at subnanomolar concentrations [197,1981. They also inhibit (Na)LiHC03 transport in human erythrocytes [199].…”

Section: + +mentioning

confidence: 99%

The regulation of the intracellular pH in cells from vertebrates

Frelin

Vigne

Ladoux

et al. 1988

European Journal of Biochemistry

302

150

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Eukaryotic cells control their intracellular pH using ion-transporting systems that are situated in the plasma membrane. This paper describes the different mechanisms that are involved and how their activity is regulated.The distribution of H + ions across the plasma membrane of most cells is such that the internal pH @Hi) is much higher than that predicted if H + were passively distributed [l]. For an average membrane potential of -60 mV and for an external pH of 7.4, a pHi value of 6.4 would be expected if H + were in electrochemical equilibrium across the membrane. Therefore, all cells have mechanisms for H + extrusion that maintain pHi at a value which is well above equilibrium and is compatible with the necessities of cytoplasmic reactions. Numerous studies performed during the last decade have demonstrated that changes in pHi occur during metabolic and developmental transitions in a large variety of cells. Acidic cytoplasmic conditions are usually associated with a quiescent or dormant cellular state while an increase in pHi often accompanies cellular activation [I, 21. These observations lead to a series of questions: (a) how is pHi regulated and how are pHi variations achieved? (b) How important is the steadystate pHi value for cell function?This paper reviews the most recent literature and focusses on two important aspects of internal pH regulation. The first aspect concerns the description of biochemically identifiable membrane ion-transport mechanisms that control pHi. One well-known mechanism is the Na+/Ht antiporter but other mechanisms also exist and they certainly play a role which has been relatively underestimated until now. The second aspect that will be discussed concerns the regulation of pHicontrolling systems.

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“…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).…”

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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Agents for the treatment of brain injury. 1. (Aryloxy)alkanoic acids

Cited by 45 publications

References 2 publications

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

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

The regulation of the intracellular pH in cells from vertebrates

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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