Doses Of Ethyl Pyruvate Research Articles

Ethyl pyruvate attenuates cisplatin-induced ovarian injury in rats via activating Nrf2 pathway

Although cisplatin (CDDP) is an antineoplastic drug widely used for the treatment of various tumors, its toxicity on the reproductive system is a concern for patients. Ethyl pyruvate (EP) possesses potent antioxidant and anti-inflammatory activities. The objective of this study was to evaluate the therapeutic potential of EP on CDDP-mediated ovotoxicity for the first time. Rats were exposed to CDDP (5 mg/kg) and then treated with two doses of EP (20 and 40 mg/kg) for 3 days. Serum fertility hormone markers were evaluated using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers were also determined. In addition, how CDDP affects the nuclear factor erythroid 2-associated factor 2 (Nrf2) pathway and the effect of EP on this situation were also addressed. EP improved CDDP-induced histopathological findings and restored decreasing levels of fertility hormones. EP treatment also reduced the levels of CDDP-mediated OS, inflammation, ERS and apoptosis. In addition, EP attenuated CDDP-induced suppression in the levels of Nrf2 and its target genes, including heme oxygenase-1, NAD(P)H quinone dehydrogenase-1, superoxide dismutase and glutathione peroxidase. Histological and biochemical results showed that EP can have therapeutic effects against CDDP-induced ovotoxicity with antioxidant, anti-inflammatory and Nrf2 activator activities.

The Effect of Ethyl Pyruvate on High Mobility Group Box I and Oxidative Stress in Induced Rheumatoid Arthritis in Rats

AbstractBackground: Rheumatoid Arthritis (RA) is autoimmune disease characterized by chronic inflammation and by the destruction of synovial joints, leading to joint deformity and disability. The cause of RA is still unknown, but several factors have been documented. These include environmental factors, genetic factors, microbial pathogens, altered levels of inflammatory mediators, and defects in immune regulation, as autoimmune disease. The response of autoimmunity can be identified by the production of autoantibodies, such as Rheumatoid Factor (RF) or Anti Citrullinated Protein Anti-bodies (ACPAs), in serum. Recently, antioxidant supplemen-tation has been the major focus of attention across the world among the health professionals to explore it as a strategy to protect against the injurious effects of oxidative stress.Aim of Study: This study aimed to investigate the beneficial effects of Ethyl Pyruvate (EP) in a rat model of Complete Freund's Adjuvant (CFA) induced RA.Material and Methods: The current study was carried out in Medical Biochemistry Department, Faculty of Medicine, Tanta University, in accordance to the guidance of Ethical Committee of Medical Research, Faculty of Medicine, Tanta University, Egypt (Approval code 31802/10/17) during 2018.The study was conducted on 60 male albino rats divided into four groups; Group I (control group), Group II (Rheuma-toid arthritis group) and Group III (treated rheumatoid arthritis group) and Group IV (EP-control group) that are received the same dose of EP in treated rheumatoid arthritis group. All groups were subjected to estimation of level of anticyclic citrullinated peptide (AntiCCP) for diagnosis of RA, inflam-matory marker as High Mobility Group Box1 (HMGB1) and Interleukin 1 Beta (IL1B) and also oxidative stress marker as Nitric Oxide (NO) and total antioxidant capacity respectively trying to detect effect of inflammation and oxidative stress in RA.Results: This study showed that EP significantly decrease Anticcp, HMGB 1 and IL1B and NO levels, also significantly in TAC.Conclusion: On basis of these results it could be concluded that EP exhibits anti-inflammatory and antioxidant effects in experimentally induced RA in rats.

Preventing intraperitoneal adhesions with ethyl pyruvate and hyaluronic acid/carboxymethylcellulose: a comparative study in an experimental model

ObjectiveTo compare the effectiveness of ethyl pyruvate (EP) with that of hyaluronic acid+carboxymethyl cellulose (Seprafilm) for the prevention of intraperitoneal adhesions. Seprafilm has been shown to be effective in many experimental and clinical studies. Study designThirty rats were divided into three groups at random, and uterine horn abrasion was performed by laparotomy. One group received no treatment (control group), one group received a single intraperitoneal dose of EP 50mg/kg (EP group), and a 2×1-cm patch of Seprafilm was applied in the third group (Seprafilm group). All rats were killed 14 days after surgery. Macroscopic and histopathological evaluation were performed by a surgeon and a pathologist who were blinded to group allocation. Histopathologically, inflammation, fibroblastic activity, foreign body reaction, collagen proliferation, vascular proliferation, Masson-Trichrome score, matrix metalloproteinase-2 score and vascular endothelial growth factor score were studied. ResultsMedian macroscopic intraperitoneal adhesion scores for the control, EP and Seprafilm groups were 2.8, 1.2 and 1.1, respectively. Multiple comparisons between groups showed a significant difference (p<0.05). In binary comparisons, significant differences were found between the control group and the EP group, and between the control group and the Seprafilm group (p<0.05). No significant difference was found between the adhesion scores for the EP group and the Seprafilm group (p>0.05). After histopathological evaluation, significant differences in all parameters were found between the groups (p<0.05). In the paired comparison, significant differences were found between the control group and the EP group, and between the control group and the Seprafilm group (p<0.0167), but no significant difference was found between the EP group and the Seprafilm group (p>0.0167). ConclusionsIn comparison with the untreated control group, EP and Seprafilm were found to reduce the formation of intraperitoneal adhesions. No significant difference was found between EP and Seprafilm.

Ethyl Pyruvate Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Intrinsic Pathway of Apoptosis and Autophagy

Background. Hepatic ischemia-reperfusion (I/R) injury is a pivotal clinical problem occurring in many clinical conditions such as transplantation, trauma, and hepatic failure after hemorrhagic shock. Apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. Ethyl pyruvate, a stable and simple lipophilic ester, has been shown to have anti-inflammatory properties. In this study, the purpose is to explore both the effect of ethyl pyruvate on hepatic I/R injury and regulation of intrinsic pathway of apoptosis and autophagy. Methods. Three doses of ethyl pyruvate (20 mg/kg, 40 mg/kg, and 80 mg/kg) were administered 1 h before a model of segmental (70%) hepatic warm ischemia was established in Balb/c mice. All serum and liver tissues were obtained at three different time points (4 h, 8 h, and 16 h). Results. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and pathological features were significantly ameliorated by ethyl pyruvate (80 mg/kg). The expression of Bcl-2, Bax, Beclin-1, and LC3, which play an important role in the regulation of intrinsic pathway of apoptosis and autophagy, was also obviously decreased by ethyl pyruvate (80 mg/kg). Furthermore, ethyl pyruvate inhibited the HMGB1/TLR4/ NF-κb axis and the release of cytokines (TNF-α and IL-6). Conclusion. Our results showed that ethyl pyruvate might attenuate to hepatic I/R injury by inhibiting intrinsic pathway of apoptosis and autophagy, mediated partly through downregulation of HMGB1/TLR4/ NF-κb axis and the competitive interaction with Beclin-1 of HMGB1.

Ethyl Pyruvate Inhibits Pancreatic Tumor Growth in Mice

Abstract Objective: We evaluate the anti-tumor effect of Ethyl Pyruvate (EP) on the human pancreatic cancer xenograft in nude mice. Methods: Human pancreatic cancer cell line SW1990 was used in vivo to investigate the effect of EP on the human pancreatic cancer in mice. The mice were treated with different doses of EP (100 mg/kg, 50 mg/kg, i. p. ) initiating 1 hour (early treatment) after tumor cells injection daily for 14 days, and EP (100 mg/kg, i. p. ) was administered beginning12 days (delayed treatment) after tumor cells injection daily for 14 days. Tumor volumes were measured. ELISA was used to measure tumor necrosis factor (TNF) -α, interleukin (IL) -1β, IL-6 and high mobility group box 1 (HMGB1). Results: EP administration inhibited pancreatic tumor growth significantly. The differences in tumor volumes were statistical significant (P=0.0001) and in tumor weights (P=0.0028) between treatment and untreated groups. Treatment with the higher (100 mg/kg) dose of EP conferred better efficacy than lower (50 mg/kg) group (P=0.024). Early treatment with EP inhibited tumor significantly than delayed treatment (P=0.001). Early administration of EP inhibits TNF-α, IL-1β, IL-6 and HMGB1 release. Conclusions: EP may have potential as a therapeutic candidate for the treatment of pancreatic cancer.

In vivo anticoagulant effect of ethyl pyruvate in endotoxemic rats

Introduction Disseminated intravascular coagulation (DIC), a disorder of the blood coagulation function, is a common complication of severe sepsis. Ethyl pyruvate (EP), a derivative of pyruvate, is known for its anti-inflammatory and antioxidant properties. Recently, EP showed anticoagulant effects in vitro. Therefore, the aim of study is to investigate the in vivo anticoagulant effect of EP on a severe DIC model induced by lipopolysaccharide (LPS) in anesthetized Wistar rats. Materials and Methods The animals were intravenously infused with LPS (30 mg/kg) over a period of 4 h. One hour after LPS initiation, rats were treated with EP in three dosages (20, 40 and 60 mg/kg/4 h, i.v.). Results The intermediate and high doses of EP (40 and 60 mg/kg) prevented circulatory failure, improved renal and hepatic function, and reduced the plasma levels of TNF-α and IL-6 after LPS administration. All used doses of EP significantly prevented prothrombin time prolongation, and reduced mRNA expression of tissue factor in lung tissue induced by LPS. The two higher doses of EP attenuated plasma concentrations of thrombin-antithrombin complex. The high dose of EP (60 mg/kg) significantly preserved platelet counts, and improved survival rate. However, EP did not reduce the elevation of plasma plasminogen activator inhibitor-1 during endotoxemia. Conclusion EP demonstrates the in vivo anticoagulant effect and improved organ functions in a severe DIC model in rats, which is likely associated with the inhibitory effect on tissue factor mRNA expression and cytokines release. Its effectiveness in preventing DIC is not mediated by increase in fibrinolysis.

Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses

Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti-inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses. Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro. Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL-1β and IL-6 was assessed. There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL-1β and IL-6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested. We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration. Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.

Ethyl pyruvate decreased early nuclear factor-κB levels but worsened survival in lipopolysaccharide-challenged mice*

Ethyl pyruvate (EP) treatment inhibits nuclear factor (NF)-kappaB-mediated inflammation and has been considered for sepsis. However, NF-kappaB is also protective, and its inhibition may have adverse effects. We studied EP in lipopolysaccharide-challenged mice and systematically analyzed its efficacy in published sepsis models. After lipopolysaccharide, compared with placebo (n = 68), each of six doses of EP (0.01-100 mg/kg, n = 204) increased the hazards ratio of death. Although these increases were individually not significant (p = .13 to .37), when combined, they were (log mean +/- SEM, 0.26 +/- 0.13; p = .01). At 3 and 9 hrs after challenge, lipopolysaccharide increased lung NF-kappaB and 12 serum cytokines (p < or = .05 vs. phosphate-buffered saline challenge, except for interleukin-4 at 9 hrs). With lipopolysaccharide, although EP (100 mg/kg) decreased NF-kappaB and 11 of 12 cytokines at 3 hrs, it increased NF-kappaB and 11 of 12 cytokines at 9 hrs in patterns that differed (p < or = .05) across time points. In 14 published comparisons, EP's effects on the odds ratio of death varied (I2 = 85% [95% confidence interval, 74-91%], p < .0001), decreasing it significantly in five of the studies but not the other nine. In three of the latter, it increased time to death. Although EP has had promising effects in some preclinical sepsis models, it has not in others, and in the present model, it worsened outcome. Based on the complex role NF-kappaB has regulating both maladaptive and protective host responses, further defining factors that influence EP's effects is important if this agent is considered for patients with or at risk of sepsis.

The effect of ethyl pyruvate on dapsone-induced methemoglobinemia in rats

Introduction. Dapsone induces methemoglobinemia by oxidant stress; ethyl pyruvate (EP) is an antioxidant and radical oxygen species scavenger. This study was conducted to evaluate the effect of EP on methemoglobinemia induced by dapsone. Methods. Male Sprague–Dawley rats were divided into an EP group and a control group. Rats in the EP group were administered dapsone (40 mg/kg) via the stomach and then EP (40 mg/kg) was injected intraperitoneally. Rats in the control group were administered dapsone followed by Ringer's lactate solution. Methemoglobin concentrations were measured at 90, 180, and 360 min after dapsone administration. Results. Methemoglobin concentrations were not different between time points in the control group. However, in the EP group, the methemoglobin concentrations were significantly lower than those of the control group at 90 and 180 min, but this difference was no longer apparent at 360 min. Conclusion. A single intraperitoneal dose of EP was able to reduce methemoglobinemia induced by dapsone for a short period of time, but this effect was not sustained.

Ethyl pyruvate ameliorates ileus induced by bowel manipulation in mice

Ethyl pyruvate (EP) improves survival, decreases proinflammatory cytokine expression, and ameliorates organ dysfunction in mice who have lethal sepsis or were subjected to hemorrhagic shock. Herein, we tested the hypothesis that treatment with EP can prevent the development of ileus after bowel manipulation, a phenomenon that is mediated by an inflammatory response in the bowel wall. C57Bl/6 mice underwent operative manipulation of the small intestine or were subjected to a sham procedure. Some of the mice subjected to gut manipulation were pre- and post-treated with 4 doses of EP (40 or 80 mg/kg per dose), whereas others received similar volumes of the vehicle for EP. Gastrointestinal transit of a nonabsorbable marker was assessed by gavaging the mice with the tracer 24 hours after operation and assessing its concentration 90 minutes later in bowel contents from the stomach, 10 equally long segments of small intestine, the cecum, and 2 equally long segments of colon. The contractile responses of ileal circular smooth muscle to graded concentrations of bethanechol were assessed by using standard organ bath methodology. Expression of interleukin-6 and inducible nitric oxide synthase transcripts in ileal muscularis propria was assessed by using the semiquantitative reverse transcriptase-polymerase chain reaction. In sham-operated controls, the mean (+/- SE) geometric center for the transit marker was 10.0 +/- 0.5, whereas for vehicle-treated mice subject to bowel manipulation, the value for this parameter was 3.5 +/- 0.1 (P < .05). When mice subjected to bowel manipulation were treated with several 40 mg/kg doses of EP, the geometric center was 7.3 +/- 1.0 (P < .05 vs sham-operated group). Gut manipulation impaired intestinal smooth muscle contractility in vitro and increased steady-state levels of interleukin-6 and inducible nitric oxide synthase messenger RNA. Treatment with EP ameliorated these effects of gut manipulation. EP warrants further evaluation as a therapeutic agent to ameliorate postoperative ileus.

Ethyl Pyruvate Ameliorates Liver Ischemia-Reperfusion Injury by Decreasing Hepatic Necrosis and Apoptosis

Hepatic ischemia-reperfusion injury (I/R) occurs in the settings of transplantation, trauma, and elective liver resections. Reactive oxygen species (ROS) have been shown to play a major role in organ I/R injury. Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. The purpose of this study was to test the hypothesis that ethyl pyruvate (EP), a soluble pyruvate derivative, is effective in preventing hepatic I/R injury. Lewis rats underwent 60 minutes of partial warm hepatic ischemia. Three doses of EP dissolved in lactated Ringer's solution or lactated Ringer's solution (LR) alone were given by intravenous injection. Serum and tissue samples were obtained at 1 to 24 hours postreperfusion. Serum transaminases, degree of hepatic necrosis, and neutrophil infiltration were all significantly decreased in the EP-treated rats compared with control animals. The amount of hepatic lipid peroxidation was also significantly decreased in EP-treated animals. Both circulating levels and hepatic expression of inflammatory cytokines were significantly decreased in the EP-treated animals. Furthermore, EP inhibited activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases, as well as nuclear factor-kappaB, signaling pathways involved in cytokine release. Treatment with EP also inhibited hepatic apoptosis. EP has a protective effect on hepatic I/R injury, mediated in part by decreasing lipid peroxidation, down-regulation of inflammatory mediators, and inhibition of apoptosis. Strategies using this additive to LR solution should be considered in clinical settings of ischemic liver injury to decrease organ damage.

Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis.

Ethyl pyruvate has been shown to be an effective anti-inflammatory agent in a variety of in vitro and in vivo model systems. Herein, we used a murine model of acute pancreatitis to compare the effects of treatment with either Ringer's lactate solution or ethyl pyruvate solution on several physiologic and biochemical variables related to disease severity. Experimental animal study. University laboratory. C57Bl/6 mice. Pancreatitis was induced by feeding the animals a choline-deficient diet supplemented with 0.5% ethionine for 24 hrs and then challenging the animals with seven hourly 50 microg/kg intraperitoneal injections of cerulein and a single intraperitoneal injection of Escherichia coli lipopolysaccharide (4 mg/kg). When mice were treated with ethyl pyruvate (40 mg/kg intraperitoneally every 6 hrs for 48 hrs) instead of Ringer's lactate solution starting 2 hrs after the injection of lipopolysaccharide, long-term survival was improved from one of ten to six of ten (p =.057). When mice were treated with a 40 mg/kg dose of ethyl pyruvate just before the first dose of cerulein and then injected with a second 40 mg/kg dose 6 hrs later, serum concentrations of alanine aminotransferase measured 10 hrs after the first cerulein dose were significantly lower than in mice with pancreatitis treated with Ringer's lactate solution. In this model of acute pancreatitis, the same dosing regimen for ethyl pyruvate also ameliorated bacterial translocation to mesenteric lymph nodes and leakage of fluorescein isothiocyanate-labeled albumin from blood into bronchoalveolar lavage fluid. Treatment with ethyl pyruvate decreased pancreatic expression of tumor necrosis factor and interleukin-6 messenger RNA and nuclear factor-kappaB DNA binding in nuclear extracts prepared from pancreatic tissue. Treatment with ethyl pyruvate ameliorated the local inflammatory response and decreased local and distant organ injury in a murine model of necrotizing pancreatitis.

Ethyl pyruvate provides durable protection against inflammation-induced intestinal epithelial barrier dysfunction.

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.