Improved Recovery from a Traumatic-Hypoxic Brain Injury in Cats by Intracisternal Injection of an Anion Transport Inhibitor

Kimelberg, Harold K.; Cragoe, Edward J.; Nelson, Louis R.; Popp, Alexander; Szarowski, D.; Rose, J.W.; Woltersdorf, Otto W.; Pietruszkiewicz, A. M.

doi:10.1089/cns.1987.4.3

Cited by 32 publications

(19 citation statements)

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“…Also, this release is inhibited by a number of anion transport blockers, including one compound that we have found significantly improves recovery in an experimental brain trauma/hypoxia model Kimelberg et al, 1987). In addition, we show that such swelling does not affect reuptake of 3H-L-glutamate upon return of the cells to isotonic media, and it is not associated with loss of cell viability as measured by staining with trypan blue, or changes in cell growth.…”

mentioning

confidence: 67%

Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

et al. 1990

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confidence: 67%

Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

et al. 1990

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“…We first injected the compound intracisternally because we assumed that as a fully charged anion at physiological pH it will not effectively cross the BBB. We had previously seen this for a related compound (L-644,711), where the dose required to effectively reduce the mortality from closed head injury in cats was about 100 fold less than that needed if the drug was given intravenously (Kimelberg et al, 1987). The simplest interpretation of the data was that the drug did not cross the BBB, or at least in sufficient amounts to be effective in the TBI model.…”

Section: Discussionmentioning

confidence: 99%

“…at a 200 fold greater amount than when given i.c. (Kimelberg et al, 1987). Possibly a higher dose of DCPIB would be effective when injected intravenously.…”

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).…”

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

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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“…Osmosensitive taurine release appears to occur via a volume-sensitive organic anion channel and is blocked by anion channel inhibitors (39). Interestingly, one such inhibitor significantly improves recovery in an experimental model for brain trauma/hypoxia (40). In cultured astrocytes, a 50% decrease in osmolarity leads to a 40-fold increase in taurine efflux rate (35).…”

Section: Discussionmentioning

confidence: 99%

Taurine Biosynthesis by Neurons and Astrocytes

Vitvitsky

Garg

Banerjee

2011

Journal of Biological Chemistry

103

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The physiological roles of taurine, a product of cysteine degradation and one of the most abundant amino acids in the body, remain elusive. Taurine deficiency leads to heart dysfunction, brain development abnormalities, retinal degradation, and other pathologies. The taurine synthetic pathway is proposed to be incomplete in astrocytes and neurons, and metabolic cooperation between these cell types is reportedly needed to complete the pathway. In this study, we analyzed taurine synthesis capability as reported by incorporation of radioactivity from [ 35 S]cysteine into taurine, in primary murine astrocytes and neurons, and in several transformed cell lines (human (SH-SY5Y) and murine (N1E-115) neuroblastoma, human astrocytoma (U-87MG and 1321 N1), and rat glioma (C6)). Extensive incorporation of radioactivity from [35 S]cysteine into taurine was observed in rat glioma cells as well as in primary mouse astrocytes and neurons, establishing the presence of an intact taurine synthesis pathway in these cells. Interestingly, exposure of cells to cysteine or cysteamine resulted in elevated intracellular hypotaurine without a corresponding increase in taurine levels, suggesting that oxidation of hypotaurine limits taurine synthesis in cells. Consistent with its role as an organic osmolyte, taurine synthesis was stimulated under hypertonic conditions in neurons.Taurine, or ethanesulfonic acid, is one of the most abundant amino acids in the body whose physiological role remains elusive. Its biosynthesis involves the sequential oxidation of cysteine to cysteinesulfinic acid, catalyzed by cysteine dioxygenase, decarboxylation by cysteinesulfinate decarboxylase, and oxidation of the resulting hypotaurine to taurine by a putative hypotaurine dehydrogenase (Fig. 1). The latter enzyme has, however, not been purified to homogeneity and remains uncharacterized (1-3). In fact, it has been suggested that oxidation of hypotaurine to taurine might occur via a nonenzymatic reaction in cells (4 -6). Hypotaurine can also be produced via oxidation of cysteamine, the end product of coenzyme A degradation (Fig. 1). Cysteamine oxidation is catalyzed by 2-aminoethanethiol dioxygenase, which is widely expressed in mammalian tissues (7).Although it is generally believed that taurine cannot be further metabolized and is excreted by the kidney or as a bile component, there are several older reports in the literature on the conversion of taurine to isethionic acid in mammalian tissues (8 -11). Various roles have been ascribed to taurine, including regulation of osmotic pressure (12-14), neuromodulatory (3, 15) and immunomodulatory (16) factors, and as an antioxidant for detoxifying hypochlorous acid, forming taurine chloramine (12). Taurine deficiency is associated with heart dysfunction, brain development abnormalities, retinal degradation, and other pathologies (3, 17). Taurine is actively transported into cells by a specific Na ϩ -dependent transporter (TAUT) and accumulates to high concentrations particularly in the liver, muscle, and retina. ...

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Improved Recovery from a Traumatic-Hypoxic Brain Injury in Cats by Intracisternal Injection of an Anion Transport Inhibitor

Cited by 32 publications

References 4 publications

Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

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

Taurine Biosynthesis by Neurons and Astrocytes

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