Zur Kenntnis der Reihe der normalen aliphatischen β‐Oxysäuren und der α‐Ketosäuren

Adickes, F.; Andresen, Geir

doi:10.1002/jlac.19445550105

Cited by 32 publications

(11 citation statements)

References 5 publications

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“…It is well known that pyruvate is an ROS scavenger (Adickes and Andresen, 1943;Bunton, 1949;Melzer and Schmidt, 1988;Dobsak et al, 1999), and data are available suggesting that EP is as well (Varma et al, 1998;Tawadrous et al, 2002). NAC, a derivative of the amino acid L-cysteine, is both an ROS scavenger itself (Aruoma et al, 1989) and a precursor for the synthesis of the important endogenous antioxidant, GSH (Fernandez et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…One possibility is suggested by the close chemical similarity between EP and pyruvate, a compound that is known to be an effective scavenger of reactive oxygen species (ROS) (Adickes and Andresen, 1943;Bunton, 1949;Melzer and Schmidt, 1988;Dobsak et al, 1999). An oxidizing environment, particularly in the cytosol, has been implicated in the activation of proinflammatory signaling molecules, such as NF-B (Schreck et al, 1992;Oka et al, 2000;Schoonbroodt et al, 2000;Livolsi et al, 2001;Rahman et al, 2001) and p38 mitogen-activated protein kinase .…”

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confidence: 99%

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Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

Song

Kellum²,

Kaldas³

et al. 2003

J Pharmacol Exp Ther

118

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Ethyl pyruvate (EP), an effective scavenger of reactive oxygen species, is also an anti-inflammatory agent in a variety of in vivo and in vitro model systems. To gain a better understanding of the molecular basis for the anti-inflammatory effects of EP, we compared the pharmacological properties of EP and N-acetyl-L-cysteine (NAC), a well studied scavenger of reactive oxygen species and a precursor for the endogenous antioxidant glutathione (GSH). The studies were performed using RAW 264.7 murine macrophage-like cells that were stimulated with lipopolysaccharide (LPS). Although EP and NAC both inhibited LPS-induced nitric oxide and interleukin (IL)-6 secretion, the former compound was considerably more potent than the latter. EP markedly inhibited inducible nitric-oxide synthase, IL-6, and IL-10 mRNA induction, whereas the effects of NAC were minimal. EP inhibited LPS-induced nuclear factor-B DNA binding to a much greater extent than did NAC. Both compounds inhibited LPS-induced lipid peroxidation, but the two compounds had qualitatively different effects on cellular levels of GSH. Although NAC increased GSH levels, EP had the opposite effect. The anti-inflammatory effects of EP were partially reversed when RAW 264.7 cells were treated with a cellpermeable GSH analog, glutathione ethyl ester. These data support the view that the anti-inflammatory effects of EP are mediated, at least in part, by the ability of EP to deplete cellular GSH stores. Moreover, the findings presented here suggest that an unusual combination of biochemical effects (inhibition of lipid peroxidation and GSH depletion) might account for the anti-inflammatory effects of EP.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

Song

Kellum²,

Kaldas³

et al. 2003

J Pharmacol Exp Ther

118

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“…This concept was predicated on the recognition that treatment with pyruvate has been shown to ameliorate organ injury or dysfunction in a variety of animal models of redox stress, such as myocardial (7), intestinal (8), or hepatic (9) ischemia/reperfusion-induced injury and glycerol-induced renal failure (10). The beneficial effects of pyruvate have been attributed to its ability to act as a scavenger of the potent reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ) (11)(12)(13)(14) and hydroxyl radical (OH) (14). However, the utility of pyruvate as a therapeutic agent may be limited by its poor stability in solution.…”

Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Provides Durable Protection Against Inflammation-Induced Intestinal Epithelial Barrier Dysfunction

Sappington¹,

Fink²,

Yang³

et al. 2003

Shock

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Ethyl pyruvate (EP) has been shown to be an effective anti-inflammatory agent. Herein, we sought to test the following hypotheses: 1) the pharmacological effects of EP persist after cells have been exposed to the compound in vitro, even if the cultures are washed to minimize the amount of EP that is retained in the media; 2) the pharmacological effects of EP persist in vivo, even after waiting a prolonged period (i.e., 6 h) after the last dose of the compound; and 3) the in vivo pharmacological effects of EP are distinct from those of the closely related compound, sodium pyruvate. Incubation of Caco-2 human enterocyte-like monolayers with cytomix, a mixture of interleukin-1beta, interferon-gamma, and tumor necrosis factor, increased permeability to the fluorescent macromolecule, FITC-labeled Dextran (mol wt 4,000 Da). Co-incubation of the cells with 5 mM EP ameliorated cytomix-induced hyperpermeability and induction of iNOS mRNA expression. EP was associated with similar pharmacological effects when cells were pre-incubated with the compound for 24 h prior and then washed extensively prior to adding the cytokine cocktail. Injecting C57Bl/6 mice with lipopolysaccharide (LPS) resulted in gut barrier dysfunction and hepatocellular injury. Although equivalent doses of both EP and sodium pyruvate ameliorated these phenomena, EP was more efficacious than pyruvate. Pretreatment with EP ameliorated the deleterious effects of LPS, even when the duration between the last dose of EP and the endotoxic challenge was 6 h. We conclude that EP provides durable protection against some of the deleterious effects of LPS or pro-inflammatory cytokines.

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“…Simple aliphatic α ‐keto carboxylates, including pyruvate, reduce hydrogen peroxide nonenzymatically in a reaction that yields carbon dioxide and water [4]. In the case of pyruvate, this reaction is both rapid and stoichiometric [5–7]. In addition to H 2 O 2 , pyruvate is also capable of scavenging another highly reactive oxygen species (ROS), hydroxyl radical (OH·) [8].…”

Section: Introductionmentioning

confidence: 99%

Ethyl pyruvate: a novel anti‐inflammatory agent

Fink

2007

Journal of Internal Medicine

150

115

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Abstract. Fink MP (University of Pittsburgh Medical School, Pittsburgh, PA, USA). Ethyl pyruvate: a novel anti-inflammatory agent (Review). J Intern Med 2007; 261: 349-362.Ethyl pyruvate (EP) is a simple derivative of the endogenous metabolite, pyruvic acid. Treatment with EP has been shown to improve survival and/or ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, such as severe sepsis, acute respiratory distress syndrome, acute pancreatitis and stroke. EP was originally regarded as simply a way to administer pyruvate anion, whilst avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including EP, have pharmacological effects, such as suppression of inflammation, that are quite distinct from those exerted by pyruvate anion. EP has been tested in human volunteers and shown to be safe at clinically relevant doses. It remains to be determined whether EP can be used successfully to treat human diseases.

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Zur Kenntnis der Reihe der normalen aliphatischen β‐Oxysäuren und der α‐Ketosäuren

Cited by 32 publications

References 5 publications

Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

Evidence That Glutathione Depletion Is a Mechanism Responsible for the Anti-Inflammatory Effects of Ethyl Pyruvate in Cultured Lipopolysaccharide-Stimulated RAW 264.7 Cells

Ethyl Pyruvate Provides Durable Protection Against Inflammation-Induced Intestinal Epithelial Barrier Dysfunction

Ethyl pyruvate: a novel anti‐inflammatory agent

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