Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats

Sims, Carrie A.; Wattanasirichaigoon, Somkiat; Menconi, Michael J.; Ajami, Alfred M.; Fink, Mitchell P.

doi:10.1097/00003246-200108000-00003

Cited by 195 publications

(160 citation statements)

References 31 publications

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“…injection of MPTP-HCl (20 mg/kg; Sigma-Aldrich) dissolved in PBS at 2-h intervals in accordance with published guidelines (14). For EP, in a Ringer's-type Ca 2+ -and K + -containing balanced salt solution (9), mice received a single injection per day of EP (10,25, and 50 mg/kg body weight; Sigma-Aldrich) into the peritoneum at 12 h after the last MPTP injection. Some mice were injected with EP alone as a control.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Ethyl Pyruvate Rescues Nigrostriatal Dopaminergic Neurons by Regulating Glial Activation in a Mouse Model of Parkinson’s Disease

Huh

Chung

Piao

et al. 2011

The Journal of Immunology

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This study examined whether ethyl pyruvate (EP) promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Western blotting and immunohistochemistry showed activation of microglial NADPH oxidase and astroglial myeloperoxidase (MPO) and subsequent reactive oxygen species/reactive nitrogen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with EP prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by EP was associated with the suppression of astroglial MPO expression, NADPH oxidase-, and/or inducible NO synthase-derived reactive oxygen species/reactive nitrogen species production by activated microglia. Interestingly, EP was found to protect DA neurons from 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present findings show that EP may inhibit glial-mediated oxidative stress, suggesting that EP may have therapeutic value in the treatment of aspects of Parkinson’s disease related to glia-derived oxidative damage.

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Section: Animals and Treatmentsmentioning

confidence: 99%

Ethyl Pyruvate Rescues Nigrostriatal Dopaminergic Neurons by Regulating Glial Activation in a Mouse Model of Parkinson’s Disease

Huh

Chung

Piao

et al. 2011

The Journal of Immunology

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“…Ethyl pyruvate (EP), a stable lipophilic pyruvate derivative identified recently by Fink and colleagues, is an experimental therapeutic that effectively protects animals from ischemia͞reperfusion-induced tissue injury (10,11). EP administration significantly improved survival in standard models of lethal hemorrhagic shock (12,13).…”

mentioning

confidence: 99%

Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation

Ulloa

Ochani

Yang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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553

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Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late [e.g., high mobility group B-1 (HMGB1)] proinflammatory cytokine response to infection. Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated. Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets. Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock. Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response. Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival ‫؍‬ 30% vs. EP survival ‫؍‬ 88%, P < 0.005). EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis. In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-B, two signaling pathways that are critical for cytokine release. This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations. EP now warrants further evaluation as an experimental ''rescue'' therapeutic for sepsis and other potentially fatal systemic inflammatory disorders.tumor necrosis factor ͉ NF-B ͉ lipopolysaccharide

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“…This study indicates that the experimental pharmacological agent EP can modulate the inflammatory response by downregulating proinflammatory cytokines and upregulating anti-inflammatory cytokines after LPS stimulation in canine PBMC cultures. Though the biochemical basis for the antiinflammatory actions of ethyl pyruvate remains to be elucidated, EP appears to have a role in protecting against lethal sepsis [10], hemorrhagic shock [8,11] and ischemia/reperfusion-induced tissue injury [2,7]. These results are based on the observed anti-inflammatory role of EP.…”

mentioning

confidence: 99%

Ethyl Pyruvate Downregulates Tumor Necrosis Factor Alpha and Interleukin (IL)-6 and Upregulates IL-10 in Lipopolysaccharide-Stimulated Canine Peripheral Blood Mononuclear Cells

Noh

Song

et al. 2010

The Journal of Veterinary Medical Science

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ABSTRACT. We investigated the anti-inflammatory effects of ethyl pyruvate (EP) on LPS-stimulated canine PBMCs in vitro. We found that EP treatment inhibited the mRNA expressions of proinflammatory cytokines (TNF- and IL-6), but induced mRNA expression of anti-inflammatory cytokines (IL-10). ELISA measurements revealed that EP also effectively downregulates the LPS-induced increase in proinflammatory cytokine release, while upregulating anti-inflammatory cytokine release. These data indicate that EP could be an effective anti-inflammatory agent in dogs.KEY WORDS: canine peripheral blood mononuclear cells, cytokine, ethyl pyruvate, mRNA.J. Vet. Med. Sci. 72(10): 1379-1381, 2010 Ethyl pyruvate (EP) is a simple aliphatic ester derived from the endogenous metabolite pyruvic acid and has been shown to exhibit antioxidant [5] and anti-inflammatory [1] properties. While EP is known to inhibit activation of p28 mitogen-activated protein kinase and NF-B in murine macrophages [10], its anti-inflammatory mechanism remains unclear.We hypothesized that lipopolysaccharide (LPS) treatment of canine PBMCs would induce proinflammatory cytokine expression and that EP would attenuate this increase at either the mRNA or protein level. To address this hypothesis, we selected TNF- and IL-6 as representative proinflammatory cytokines that are upregulated after LPS administration. In addition, we selected IL-10 as an anti-inflammatory cytokine.Blood was collected from six healthy beagles and peripheral blood mononuclear cells (PBMCs) were separated using Histopaque ) and 100 U/ml penicillin G and 10 g/ml streptomycin (Sigma) at 37C in 5% CO 2 and incubated overnight. The next day, the mononuclear cells were exposed to 100 ng/ml of LPS (Escherichia coli serotype O111: B4, Sigma) and simultaneously treated with various concentrations of EP (Sigma) (5 d 10 mM each) based on previous in vitro studies [9]. The cell pellets were used for RNA isolation, and the cell-free supernatants were stored at -80C until they were analyzed. Samples were harvested after 3, 6, 12 and 24 hr of cultivation. Unstimulated cells and cells in 10 mM ethyl pyruvate were used as controls. All procedures used in this study were approved by local animal welfare authorities (CBU2008-021).For the quantification of cytokine gene expression, SYBR ® green real-time PCR was used. Total RNA was extracted using an RNeasy The primers utilized in this study are summarized in Table 1. The optimal annealing temperature (T a ) for all assays ranged from 60C for GAPDH and IL-6 to 62C for TNF- and IL-10. Primer efficiency calculations [E (%) = (10 (1/-S) -1)  100, S=slope] for all of the standard lines were between 95.7 and 102.4%. Relative quantification was analyzed using the -2 CT method as previously described [4]. Tests were performed in duplicate.Our quantification of cytokine mRNA abundance demonstrated that EP inhibits TNF- and IL-6 mRNA synthesis and promotes IL-10 mRNA expression on LPS stimulation,

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Ringer’s ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats

Cited by 195 publications

References 31 publications

Ethyl Pyruvate Rescues Nigrostriatal Dopaminergic Neurons by Regulating Glial Activation in a Mouse Model of Parkinson’s Disease

Ethyl Pyruvate Rescues Nigrostriatal Dopaminergic Neurons by Regulating Glial Activation in a Mouse Model of Parkinson’s Disease

Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation

Ethyl Pyruvate Downregulates Tumor Necrosis Factor Alpha and Interleukin (IL)-6 and Upregulates IL-10 in Lipopolysaccharide-Stimulated Canine Peripheral Blood Mononuclear Cells

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