Effects of Ethyl Pyruvate and Other α-Keto Carboxylic Acid Derivatives in a Rat Model of Multivisceral Ischemia and Reperfusion
Effects of Ethyl Pyruvate and Other α-Keto Carboxylic Acid Derivatives in a Rat Model of Multivisceral Ischemia and Reperfusion
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DOI：
10.1016/j.jss.2009.07.008
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发表时间：
2011-01-01
影响因子：
2.2
通讯作者：
Fink, Mitchell P.
中科院分区：
文献类型：
--
作者：
Cruz, Ruy J., Jr.;Harada, Tomoyuki;Fink, Mitchell P.
背景丙酮酸乙酯（EP）已被证明可以改善肝、肾和肠粘膜损伤，并在多种危重疾病的临床前模型（如脓毒症、烧伤、急性胰腺炎、中风和出血性休克）中下调几种促炎介质的表达。负责EP的治疗作用的分子机制仍然知之甚少，但可能与化合物的α-酮羧酸酯结构有关。在此，我们测试了EP和其他α-酮羧酸衍生物可以调节下躯干缺血/再灌注（I/R）后器官损伤的假设。大鼠腹腔上主动脉阻断50分钟。在20分钟的时间内，从释放主动脉夹前2分钟开始，动物接受2 μ L/g的林格氏乳酸盐溶液（RL，n = 5）或等体积的含有EP（n = 5）、苯甲酰甲酸盐（BF，n = 5）、对羟基苯基丙酮酸盐（PHPP，n = 5）或丙酮酸钠（NaPyr，n = 5）的溶液。每种化合物的总剂量为0.86 mMol/kg。再灌注1小时后，我们测量回肠粘膜对荧光素标记的葡聚糖（分子量4000 Da）的通透性，肝脏丙二醛（MDA）含量，以及血浆丙氨酸氨基转移酶（ALT）和TNF水平。对照组（CT组，n = 4）行腹腔上主动脉切开术，但不行内脏I/R。与CT组相比，RL组回肠粘膜通透性、血浆ALT和TNF水平以及肝脏MDA含量显著增加。EP和BF均显著改善全身动脉低血压、粘膜通透性增高的发展，并显著降低血浆TNF水平。EP、PHPP、BF和NaPy均能显著降低MDA含量。通常，EP在该模型中比NaPyr更有效。虽然EP和丙酮酸之间的药理学差异还有待进一步了解，但一个重要因素可能是前者化合物的亲脂性更大。这一见解可能允许开发更有效的细胞保护剂和抗炎剂的基础上的乙酰基部分。(C)2011 Elsevier Inc. All rights reserved.
Background. Ethyl pyruvate (EP) has been shown to ameliorate hepatic, renal, and intestinal mucosal injury and down-regulate expression of several pro-inflammatory mediators in a wide variety of preclinical models of critical illnesses, such as sepsis, burn injury, acute pancreatitis, stroke, and hemorrhagic shock. The molecular mechanisms responsible for the therapeutic effects of EP remain poorly understood, but might be related to the compound's structure as the ester of an alpha-keto carboxylic acid. Herein, we tested the hypothesis that EP and other alpha-keto carboxylic acid derivatives can modulate organ injury after lower torso ischemia/reperfusion (I/R).Methods. Rats were subjected to 50min of supraceliac aortic occlusion. Over a 20-min period, starting 2min before the release of the aortic clamp, the animals received 2 mu L/g of Ringer's lactate solution (RL, n = 5) or an equivalent volume of a solution containing EP (n = 5), benzoyl formate (BF, n = 5), parahydroxyphenyl pyruvate (PHPP, n = 5) or sodium pyruvate (NaPyr, n = 5). The total dose of each compound was 0.86 mMol/kg. After 1h of reperfusion, we measured ileal mucosal permeability to fluorescein-labeled dextran (mw 4000 Da), liver malondialdehyde (MDA) content, and plasma levels of alanine aminotransferase (ALT) and TNF. Rats in the control group (CT, n = 4) were subjected to laparotomy and surgical isolation of the supraceliac aorta, but not visceral I/R.Results. Ileal mucosal permeability, plasma levels of ALT and TNF, and hepatic MDA content increased significantly in the RL group relative to the CT group. Both EP and BF significantly ameliorated the development of systemic arterial hypotension, mucosal hyper-permeability, and significantly decreased plasma levels of TNF. MDA content was significantly decreased by EP, PHPP, BF, and NaPyr.Conclusions. In general, EP is more efficacious in this model than is NaPyr. Although more remains to be learned about the pharmacologic differences between EP and pyruvate, one important factor may the greater lipophilicity of the former compound. This insight may permit the development of even more effective cytoprotective and anti-inflammatory agents based on the pyruvoyl moiety. (C) 2011 Elsevier Inc. All rights reserved.