丙酮酸乙酯对新生大鼠脑缺血缺氧损伤保护作用及其机制研究
|
摘要
新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)是围产期脑损伤最常见原因,不仅威胁新生儿的生命,而且有严重的神经系统后遗症。但对新生儿缺血缺氧性脑病的治疗,目前为止国内外尚无统一、有效的治疗方案。因此,寻找治疗新生儿缺血缺氧性脑病更为有效的方法已成为围产医学中的重要课题,越来越受到医学界广大医务工作者及学者的重视。新生大鼠脑缺血缺氧模型被广泛用于研究新生期脑缺血缺氧损伤的发病机理、早期诊断指标筛选和干预方法的评枯。丙酮酸乙酯是一种安全、稳定且极易被细胞摄取的物质。2001年,Sims等研究发现林格氏丙酮酸乙酯溶液治疗肠系膜缺血再灌,能大大减轻肠粘膜结构和功能的损伤;Yang等人于2002年首次提出了丙酮酸乙酯的抗炎作用,此后对丙酮酸乙酯保护作用抗炎机制研究倍受关注。本实验在7日龄Sprague-Dawley大鼠制备的新生大鼠脑缺血缺氧损伤动物模型基础上,研究丙酮酸乙酯对新生期脑缺血缺氧损伤的作用,并探讨其作用机制。
实验结果如下:
(一)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤具有明显保护作用
1.丙酮酸乙酯对新生大鼠脑缺血缺氧保护作用具有剂量依赖性
2.丙酮酸乙酯对新生大鼠脑缺血缺氧保护作用具有时间依赖性,在缺血缺氧后30min腹腔注射依然有明显保护作用
3.丙酮酸乙酯对损伤各个脑区均有明显保护作用
(二)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤的长时程保护作用1.丙酮酸乙酯在新生大鼠脑缺血缺氧损伤后8周依然有明显保护作用
2.丙酮酸乙酯转归了新生大鼠生长发育(缺血缺氧后第2周～第8周)的行为变化
(三)丙酮酸乙酯在新生大鼠脑缺血缺氧损伤保护中的抗凋亡作用
1.抑制促凋亡因子caspase-3和AIF的激活
1)丙酮酸乙酯抑制了新生大鼠脑缺血缺氧损伤后促凋亡因子caspase-3的激活
2)丙酮酸乙酯抑制了新生大鼠脑缺血缺氧损伤后促凋亡因子AIF的核内水平
2.升高抗凋亡因子Bcl-xl水平及抗凋亡信号通路PI3K/Akt中途径p-Akt的水平
1)丙酮酸乙酯升高了新生大鼠脑缺血缺氧损伤后抗凋亡蛋白Bcl-xl的水平
2)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤保护作用机制中抗凋亡途径PI3K/Akt信号通路的作用
a)新生大鼠脑缺血缺氧损伤后大脑皮层p-Akt表达水平降低
b)丙酮酸乙酯升高了新生大鼠脑缺血缺氧损伤后大脑皮层降低的p-Akt水平
c)侧脑室注射LY294002(PI3K/Akt信号通路抑制剂)后,不能抑制丙酮酸乙酯对新生大鼠脑缺血缺氧损伤的保护
(四)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后致炎相关因子水平的升高
1.丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的细胞因子表达水平
1)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的炎症因子COX-2,iNOS,TNF-a,IL-1a,IL-1b,IL-6的mRNA水平
2)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的炎症因子COX-2蛋白水平
3)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后核内升高的转录因子NF-κB/p65的水平
2.丙酮酸乙酯抑制了新生大鼠侧脑室注射LPS诱导的炎症反应中炎症因子COX-2,iNOS的表达水平
总之,我们的研究证明了丙酮酸乙酯在新生大鼠脑缺血缺氧损伤中具有显著的保护作用。这种保护作用,至少部分,是由于抗炎作用,使NF-κB入核减少,降低其转录调控的炎症因子,如:COX-2,iNOS,TNF-α,IL-1α,IL-1β,IL-6;同时,丙酮酸乙酯具有抗凋亡作用,抑制促凋亡因子caspase-3、AIF的激活,升高抗凋亡因子Bcl-xl的表达水平,引起抗凋亡通路PI3K/Akt中p-Akt水平增高。我们的研究为临床治疗新生儿缺血缺氧性脑病提供了可能的手段和理论依据。
Background and purpose:Hypoxic-ischemic(H-I) injury in the developing brain is a major cause of morbidity and mortality associated with periventricular leukomalacia and cerebral palsy.The way of neuronal cell death caused by H-I injury includes apoptosis and necrosis. Therefore,inhibiting necrosis-mediated inflammation is very important in the neuroprotection against H-I brain injury.Ethyl pyruvate(EP),a stable lipophilic pyruvate derivative identified recently by Fink and colleagues,is an experimental therapeutic that effectively protects animals from oxidative stress injury.The mechanism may be inhibiting the inflammation pathway,down-regulating expressions of various proinflammation factors and cytokines.However,whether EP attenuates neonatal brain damage following hypoxic ischemia(H-I) remains undemonstrated,and the mechanism should be further researched.
Results:
1.Administration of EP before and after H-I insult decreases cerebral tissue loss in a dose-dependent and time-dependent manner measured 7days later.Even within 30 rain after H-I insult,EP also protects cerebral tissue loss.
2.In the long-term recovery experimental paradigms(8 weeks after H-I),the neuroprotective effect of EP remained.Administration of ethyl pyruvate also ameliorated behavioral deficits.The number of forelimb steps is different between vehicle and EP group from 3rd week.The number of backlimb steps is 4th week.
3.Ethyl pyruvate inhibited the activities of caspase-3 and AIF.And ethyl pyruvate rised the anti-apoptotic factors' levels of phospho-Akt(p-Akt) and Bcl-xl.
4.Ethyl pyruvate inhibited NF-κB activation.Then,ethyl pyruvate inhibited expressions of various proinflammation factors and cytokines which were regulated by NF-κB.
Conclusion:These results demonstrate that EP confers potent neuroprotection against neonatal H-I brain injury and that the neuroprotective effect of EP is at least partially mediated via its anti-inflammatory actions.EP is thus a potential novel therapeutic agent for neonatal H-I brain injury.
实验结果如下:
(一)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤具有明显保护作用
1.丙酮酸乙酯对新生大鼠脑缺血缺氧保护作用具有剂量依赖性
2.丙酮酸乙酯对新生大鼠脑缺血缺氧保护作用具有时间依赖性,在缺血缺氧后30min腹腔注射依然有明显保护作用
3.丙酮酸乙酯对损伤各个脑区均有明显保护作用
(二)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤的长时程保护作用1.丙酮酸乙酯在新生大鼠脑缺血缺氧损伤后8周依然有明显保护作用
2.丙酮酸乙酯转归了新生大鼠生长发育(缺血缺氧后第2周～第8周)的行为变化
(三)丙酮酸乙酯在新生大鼠脑缺血缺氧损伤保护中的抗凋亡作用
1.抑制促凋亡因子caspase-3和AIF的激活
1)丙酮酸乙酯抑制了新生大鼠脑缺血缺氧损伤后促凋亡因子caspase-3的激活
2)丙酮酸乙酯抑制了新生大鼠脑缺血缺氧损伤后促凋亡因子AIF的核内水平
2.升高抗凋亡因子Bcl-xl水平及抗凋亡信号通路PI3K/Akt中途径p-Akt的水平
1)丙酮酸乙酯升高了新生大鼠脑缺血缺氧损伤后抗凋亡蛋白Bcl-xl的水平
2)丙酮酸乙酯对新生大鼠脑缺血缺氧损伤保护作用机制中抗凋亡途径PI3K/Akt信号通路的作用
a)新生大鼠脑缺血缺氧损伤后大脑皮层p-Akt表达水平降低
b)丙酮酸乙酯升高了新生大鼠脑缺血缺氧损伤后大脑皮层降低的p-Akt水平
c)侧脑室注射LY294002(PI3K/Akt信号通路抑制剂)后,不能抑制丙酮酸乙酯对新生大鼠脑缺血缺氧损伤的保护
(四)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后致炎相关因子水平的升高
1.丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的细胞因子表达水平
1)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的炎症因子COX-2,iNOS,TNF-a,IL-1a,IL-1b,IL-6的mRNA水平
2)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后升高的炎症因子COX-2蛋白水平
3)丙酮酸乙酯降低了新生大鼠脑缺血缺氧损伤后核内升高的转录因子NF-κB/p65的水平
2.丙酮酸乙酯抑制了新生大鼠侧脑室注射LPS诱导的炎症反应中炎症因子COX-2,iNOS的表达水平
总之,我们的研究证明了丙酮酸乙酯在新生大鼠脑缺血缺氧损伤中具有显著的保护作用。这种保护作用,至少部分,是由于抗炎作用,使NF-κB入核减少,降低其转录调控的炎症因子,如:COX-2,iNOS,TNF-α,IL-1α,IL-1β,IL-6;同时,丙酮酸乙酯具有抗凋亡作用,抑制促凋亡因子caspase-3、AIF的激活,升高抗凋亡因子Bcl-xl的表达水平,引起抗凋亡通路PI3K/Akt中p-Akt水平增高。我们的研究为临床治疗新生儿缺血缺氧性脑病提供了可能的手段和理论依据。
Background and purpose:Hypoxic-ischemic(H-I) injury in the developing brain is a major cause of morbidity and mortality associated with periventricular leukomalacia and cerebral palsy.The way of neuronal cell death caused by H-I injury includes apoptosis and necrosis. Therefore,inhibiting necrosis-mediated inflammation is very important in the neuroprotection against H-I brain injury.Ethyl pyruvate(EP),a stable lipophilic pyruvate derivative identified recently by Fink and colleagues,is an experimental therapeutic that effectively protects animals from oxidative stress injury.The mechanism may be inhibiting the inflammation pathway,down-regulating expressions of various proinflammation factors and cytokines.However,whether EP attenuates neonatal brain damage following hypoxic ischemia(H-I) remains undemonstrated,and the mechanism should be further researched.
Results:
1.Administration of EP before and after H-I insult decreases cerebral tissue loss in a dose-dependent and time-dependent manner measured 7days later.Even within 30 rain after H-I insult,EP also protects cerebral tissue loss.
2.In the long-term recovery experimental paradigms(8 weeks after H-I),the neuroprotective effect of EP remained.Administration of ethyl pyruvate also ameliorated behavioral deficits.The number of forelimb steps is different between vehicle and EP group from 3rd week.The number of backlimb steps is 4th week.
3.Ethyl pyruvate inhibited the activities of caspase-3 and AIF.And ethyl pyruvate rised the anti-apoptotic factors' levels of phospho-Akt(p-Akt) and Bcl-xl.
4.Ethyl pyruvate inhibited NF-κB activation.Then,ethyl pyruvate inhibited expressions of various proinflammation factors and cytokines which were regulated by NF-κB.
Conclusion:These results demonstrate that EP confers potent neuroprotection against neonatal H-I brain injury and that the neuroprotective effect of EP is at least partially mediated via its anti-inflammatory actions.EP is thus a potential novel therapeutic agent for neonatal H-I brain injury.
引文
1.Spataro,J.,Anoxic-ischemic encephalopathy of the rat brain.Exp Neurol,1966.16(1):p.16-27.
2.Vannucci,R.C.,Cerebral carbohydrate and energy metabolism in perinatal hypoxic-ischemic brain damage.Brain Pathol,1992.2(3):p.229-34.
3.Benjelloun,N.,et al.,Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat.Stroke,1999.30(9):p.1916-23;discussion 1923-4.
4.Barone,F.C.and G.Z.Feuerstein,Inflammatory mediators and stroke:new opportunities for novel therapeutics.J Cereb Blood Flow Metab,1999.19(8):p.819-34.
5.Saliba,E.and A.Henrot,Inflammatory mediators and neonatal brain damage.Biol Neonate,2001.79(3-4):p.224-7.
6.Zhu,C.,et al.,Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia.J Neurochem,2006.96(4):p.1016-27.
7.Ogawa,S.,T.M.Lee,and P.Glynn,Energy metabolism in rat brain in vivo studied by 31P nuclear magnetic resonance:changes during postnatal development.Arch Biochem Biophys,1986.248(1):p.43-52.
8.Pettegrew,J.W.,et al.,Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat.J Neuropathol Exp Neurol,1990.49(3):p.237-49.
9.Hagberg,H.,Hypoxic-ischemic damage in the neonatal brain:excitatory amino acids.Dev Pharmacol Ther,1992.18(3-4):p.139-44.
10.del Zoppo,G.,et al.,Inflammation and stroke:putative role for cytokines,adhesion molecules and iNOS in brain response to ischemia.Brain Pathol,2000.10(1):p.95-112.
11.Tak,P.P.and G.S.Firestein,NF-kappaB:a key role in inflammatory diseases.J Clin Invest,2001.107(1):p.7-11.
12.Lawrence,T.,et al.,Possible new role for NF-kappaB in the resolution of inflammation.Nat Med,2001.7(12):p.1291-7.
13.Giuliani,C.,et al.,[Nf-kB transcription factor:role in the pathogenesis of inflammatory,autoimmune,and neoplastic diseases and therapy implications].Clin Ter,2001.152(4):p.249-53.
14.Pulera,M.R.,et al.,Apoptosis in a neonatal rat model of cerebral hypoxia-ischemia.Stroke,1998.29(12):p.2622-30.
15.Liou,A.K.,et al.,To die or not to die for neurons in ischemia,traumatic brain injury and epilepsy:a review on the stress-activated signaling pathways and apoptotic pathways.Prog Neurobiol,2003.69(2):p.103-42.
16.Hill,I.E.,et al.,DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat.Brain Res,1995.676(2):p.398-403.
17.Nakajima,W.,et al.,Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat.J Neurosci,2000.20(21):p.7994-8004.
18.Northington,F.J.,et al.,Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis.J Neurosci,2001.21(6):p.1931-8.
19.Northington,F.J.,D.M.Ferriero,and L.J.Martin,Neurodegeneration in the thalamus following neonatal hypoxia-ischemia is programmed cell death.Dev Neurosci,2001.23(3):p.186-91.
20.Chen,J.,et al.,Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia.J Neurosci,1998.18(13):p.4914-28.
21.Zhang,X.,et al.,Intranuclear localization of apoptosis-inducing factor(AIF)and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite.J Neurochern,2002.82(1):p.181-91.
22.Daugas,E.,et al.,Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis.Faseb J,2000.14(5):p.729-39.
23.Cao,G.,et al.,Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation.J Cereb Blood Flow Metab,2003.23(10):p.1137-50.
24.Yin,W.,et al.,Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation.Stroke,2007.38(3):p.1017-24.
25.Yano,S.,et al.,Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus.J Cereb Blood Flow Metab,2001.21(4):p.351-60.
26.Cheng,Y.,et al.,Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury.Ann Neurol,1997.41(4):p.521-9.
27.Tomimatsu,T.,et al.,Long-term neuroprotective effects of hypothermia on neonatal hypoxic-ischemic brain injury in rats,assessed by auditory brainstem response.Pediatr Res,2003.53(1):p.57-61.
28.Adachi,M.,et al.,Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats.Pediatr Res,2001.50(5):p.590-5.
29.Han,B.H.,et al.,Selective,reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury.J Biol Chem,2002.277(33):p.30128-36.
30.Hamrick,S.E.and D.M.Ferriero,The injury response in the term newborn brain:can we neuroprotect? Curr Opin Neurol,2003.16(2):p.147-54.
31.Yin,W.,et al.,TAT-mediated delivery of Bcl-xL protein is neuroprotective against neonatal hypoxic-ischemic brain injury via inhibition of caspases and AIF.Neurobiol Dis,2006.21(2):p.358-71.
32.Das,U.N.,Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule.Med Sci Monit,2006.12(5):p.RA79-84.
33.Salahudeen,A.K.,E.C.Clark,and K.A.Nath,Hydrogen peroxide-induced renal injury.A protective role for pyruvate in vitro and in vivo.J Clin Invest,1991.88(6):p.1886-93.
34.Bunger,R.,R.T.Mallet,and D.A.Hartman,Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart.Near-complete prevention of reperfusion contractile failure.Eur J Biochem,1989.180(1):p.221-33.
35.Cicalese,L.,et al.,Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine.Am J Surg,1996.171(1):p.97-100;discussion 100-1.
36.Tsung,A.,et al.,Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis.Transplantation,2005.79(2):p.196-204.
37.Sileri,P.,et al.,Pyruvate inhibits hepatic ischemia-reperfusion injury in rats.Transplantation,2001.72(1):p.27-30.
38.Gupta,S.K.,et al.,Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells.Ophthalmic Res,2002.34(1):p.23-8.
39.Lee,J.Y.,Y.H.Kim,and J.Y.Koh,Protection by pyruvate against transient forebrain ischemia in rats.J Neurosci,2001.21(20):p.RC171.
40.Slovin,EN.,et al.,Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock.Resuscitation,2001.50(1):p.109-15.
41.Mongan,P.D.,et al.,Intravenous pyruvate prolongs survival during hemorrhagic shock in swine.Am J Physiol,1999.277(6 Pt 2):p.H2253-63.
42.Sims,C.A.,et al.,Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.Crit Care Med,2001.29(8):p.1513-8.
43.Varma,S.D.,K.R.Hegde,and S.Kovtun,Oxidative damage to lens in culture:reversibility by pyruvate and ethylpyruvate.Ophthalmologica,2006.220(1):p.52-7.
44.Mulier,K.E.,et al.,Ringer's ethyl pyruvate in hemorrhagic shock and resuscitation does not improve early hemodynamics or tissue energetics.Shock,2005.23(3):p.248-52.
45.Sappington,P.L.,et al.,Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers.J Pharmacol Exp Ther,2003.304(1):p.464-76.
46.Tsai,B.M.,et al.,Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression.J Surg Res,2008.145(1):p.130-4.
47.Zingarelli,B.,Ethyl pyruvate:a simple solution? Crit Care Med,2004.32(7):p. 1603-4.
48.Yang,R.,et al.,Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock.Am J Physiol Gastrointest Liver Physiol,2002.283(1):p.G212-21.
49.Taylor,M.D.,et al.,Ethyl pyruvate enhances ATP levels,reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass.Heart Lung Circ,2005.14(1):p.25-31.
50.Tawadrous,Z.S.,R.L.Delude,and M.P.Fink,Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats.Shock,2002.17(6):p.473-7.
51.Venkataraman,R.,et al.,Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock.Shock,2002.18(6):p.507-12.
52.Song,M.,et al.,Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells.J Pharmacol Exp Ther,2004.308(1):p.307-16.
53.Miyaji,T.,et al.,Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice.Kidney Int,2003.64(5):p.1620-31.
54.Han,Y.,et al.,Ethyl pyruvate inhibits nuclear faetor-kappaB-dependent signaling by directly targeting p65.J Pharmacol Exp Ther,2005.312(3):p.1097-105.
55.Wang,H.,et al.,HMGB1 as a potential therapeutic target.Novartis Found Symp,2007.280:p.73-85;discussion 85-91,160-4.
56.Wang,L.Z.,W.C.Sun,and X.Z.Zhu,Ethyl pyruvate protects PC12 cells from dopamine-induced apoptosis.Eur J Pharmacol,2005.508(1-3):p.57-68.
57.Yang,R.,et al.,Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice.J Lab Clin Med,2003.142(5):p.322-31.
58.Cheng,B.Q.,et al.,Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis.Pancreas,2007.35(3):p.256-61.
59.Fink,M.P.,Ethylpyruvate:a novel anti-inflammatory agent.J Intern Med,2007. 261(4):p.349-62.
60.Yang,R.,et al.,Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizingpancreatitis.Crit Care Med,2004.32(7):p.1453-9.
61.Fink,M.P.,Ethyl pyruvate:a novel treatment for sepsis.Novartis Found Symp,2007.280:p.147-56;discussion 156-64.
62.Kim,J.B.,et al.,Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain.Brain Res,2005.1060(1-2):p.188-92.
63.Cho,I.H.,et al.,Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus.J Neurosci Res,2006.84(7):p.1505-11.
64.Yu,Y.M.,et al.,Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window.Stroke,2005.36(10):p.2238-43.
65.Rice,J.E.,3rd,R.C.Vannucci,and J.B.Brierley,The influence of immaturity on hypoxic-ischemic brain damage in the rat.Ann Neurol,1981.9(2):p.131-41.
66.Levine,S.,Anoxic-ischemic encephalopathy in rats.Am J Pathol,1960.36:p.1-17.
67.Asoh,S.,et al.,Protection against ischemic brain injury by protein therapeutics.Proc Natl Acad Sci U S A,2002.99(26):p.17107-12.
68.Bona,E.,et al.,Protective effects of moderate hypothermia after neonatal hypoxia-ischemia:short- and long-term outcome.Pediatr Res,1998.43(6):p.738-45.
69.Lubics,A.,et al.,Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury.Behav Brain Res,2005.157(1):p.157-65.
70.Chen,J.,et al.,Early detection of DNA strand breaks in the brain after transient focal ischemia:implications for the role of DNA damage in apoptosis and neuronal cell death.J Neurochem,1997.69(1):p.232-45.
71.Hu,Y.,et al.,Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation.Proc Natl Acad Sci U S A,1998.95(8):p.4386-91.
72.Parsadanian,A.S.,et al.,Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons.J Neurosci,1998.18(3):p.1009-19.
73.Senftleben,U.and M.Karin,The IKK/NF-kappa B pathway.Crit Care Med,2002.30(1 Suppl):p.S18-26.
74.Milatovic,D.,et al.,Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum.J Neurochem,2003.87(6):p.1518-26.
75.Silverstein,F.S.,B.Naik,and J.Simpson,Hypoxia-ischemia stimulates hippocampal glutamate efflux in perinatal rat brain:an in vivo microdialysis study.Pediatr Res,1991.30(6):p.587-90.
76.Gordon,K.E.,et al.,Effects of perinatal stroke on striatal amino acid efflux in rats studied with in vivo microdialysis.Stroke,1991.22(7):p.928-32.
77.Thoresen,M.and J.Wyatt,Keeping a cool head,post-hypoxic hypothermia--an old idea revisited.Acta Paediatr,1997.86(10):p.1029-33.
78.Vannucci,R.C.,et al.,Measuring the accentuation of the brain damage that arises from perinatal cerebral hypoxia-ischemia.Biol Neonate,1997.72(3):p.187-91.
79.Fernandez-Gomez,F.J.,et al.,Pyruvate protects cerebellar granular cells from 6-hydroxydopamine-induced cytotoxicity by activating the Akt signaling pathway and increasing glutathione peroxidase expression.Neurobiol Dis,2006.24(2):p.296-307.
80.Ulloa,L.,et al.,Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci U S A,2002.99(19):p.12351-6.
1.Mitchell RFink,MD,FCCM.Ethyl pyruvate:A novel anti-inflammatory agent.Crit.Care.Med.31(1 suppl):s51-s56(2003)
2.Salahudeen AK,Clark EC,Nath KA:Hydrogenperoxide-induced renal injury:A protectiverole for pyruvate in vitro and in vivo.J Clin Invest 1991;88:1886-1893
3.Bunger R,Mallet RT,Hartman DA:Pyruvate enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart:Near-complete prevention of reperfusion contractile failure.Eur J Bioehem 1989;180:221-233
4.Cicalese L,Lee K,Schraut W,et al:Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine.Am J Surg 1999;171:97-100
5.Sileri P,Schena S,Morini S,et al:Pyruvate inhibits hepatic ischemia-reperfusion injury in rats.Transplantation 2001;72:27-30
6.Gupta SK,Mohanty I,Trivedi D,et al:Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells.Ophthalmic Res 2002;34:23-28
7.Lee JY,Kim YH,Koh JY:Protection by pyruvate against transient forebrain ischemia in rats.J Neurosci 2002;21:1-6
8.Slovin PN,Huang CJ,Cade JR,et al:Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock.Resuscitation 2001;50:109-115
9.Mongan PD,Capacchione J,Fontana JL,et al:Pyruvate improves cerebral metabolism during hemorrhagic shock.Am J Physio12001;281:H854-H864
10.Mongan PD,Fontana JL,Chen R,et al:Intravenous pyruvate prolongs survival during hemorrhagic shock in swine.Am J Physiol 1999;277:H2253-H2263
11.Sims CA,Wattanasirichaigoon S,Menconi MJ,et al:Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.Crit Care Med 2001;29:1513-1518
12.Varma SD,Devamanoharan PS,Ali AH:Prevention of intracellular oxidative stress to lens by pyruvate and its ester.Free Rad Res 1998;28:131-135
13.Tawadrous ZS,Delude RL,Fink MP:Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats.Shock 2002;17:473-477
14.Yang R,Gallo DJ,Baust JJ,et al:Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock.Am J Physiol Gastrointest Liver Physio12002;283:G212-G22
15.Venkataraman R,Kellum JA,Song M,et al:Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharideinduced shock.Shock In Press
16.Ulloa L,Ochani M,Yang H,et al:Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci USA 2002;99:12351-12356
17.Wang,L.Z.,W.C.Sun,and X.Z.Zhu,Ethyl pyruvate protects PC12 cells from dopamine-induced apoptosis.Eur J Pharmacol,2005.508(1-3):p.57-68.
18.Cho,I.H.,et al.,Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus.J Neurosci Res,2006.84(7):p.1505-11.
19.金晶:NF.KB的研究进展.国外医学药学分册2000;27(3):131-137
20.Schoonbroodt S,Ferreira V,Best-Belpomme M,et al:Crucial role of the amino-terminal tyrosine residue 42 and the carboxylterminal PEST domain of IkBa in NF-kB activation by oxidative stress. J Immunol 2000; 164:4292-4300
21.Yusheng Han,Mitchell et al: ethyle pyruvate inhibits NF-κB-dependent signaling by directly targeting p65. JPET Fast Forward; Published on November 3,2004
2.Vannucci,R.C.,Cerebral carbohydrate and energy metabolism in perinatal hypoxic-ischemic brain damage.Brain Pathol,1992.2(3):p.229-34.
3.Benjelloun,N.,et al.,Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat.Stroke,1999.30(9):p.1916-23;discussion 1923-4.
4.Barone,F.C.and G.Z.Feuerstein,Inflammatory mediators and stroke:new opportunities for novel therapeutics.J Cereb Blood Flow Metab,1999.19(8):p.819-34.
5.Saliba,E.and A.Henrot,Inflammatory mediators and neonatal brain damage.Biol Neonate,2001.79(3-4):p.224-7.
6.Zhu,C.,et al.,Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia.J Neurochem,2006.96(4):p.1016-27.
7.Ogawa,S.,T.M.Lee,and P.Glynn,Energy metabolism in rat brain in vivo studied by 31P nuclear magnetic resonance:changes during postnatal development.Arch Biochem Biophys,1986.248(1):p.43-52.
8.Pettegrew,J.W.,et al.,Changes in brain energy and phospholipid metabolism during development and aging in the Fischer 344 rat.J Neuropathol Exp Neurol,1990.49(3):p.237-49.
9.Hagberg,H.,Hypoxic-ischemic damage in the neonatal brain:excitatory amino acids.Dev Pharmacol Ther,1992.18(3-4):p.139-44.
10.del Zoppo,G.,et al.,Inflammation and stroke:putative role for cytokines,adhesion molecules and iNOS in brain response to ischemia.Brain Pathol,2000.10(1):p.95-112.
11.Tak,P.P.and G.S.Firestein,NF-kappaB:a key role in inflammatory diseases.J Clin Invest,2001.107(1):p.7-11.
12.Lawrence,T.,et al.,Possible new role for NF-kappaB in the resolution of inflammation.Nat Med,2001.7(12):p.1291-7.
13.Giuliani,C.,et al.,[Nf-kB transcription factor:role in the pathogenesis of inflammatory,autoimmune,and neoplastic diseases and therapy implications].Clin Ter,2001.152(4):p.249-53.
14.Pulera,M.R.,et al.,Apoptosis in a neonatal rat model of cerebral hypoxia-ischemia.Stroke,1998.29(12):p.2622-30.
15.Liou,A.K.,et al.,To die or not to die for neurons in ischemia,traumatic brain injury and epilepsy:a review on the stress-activated signaling pathways and apoptotic pathways.Prog Neurobiol,2003.69(2):p.103-42.
16.Hill,I.E.,et al.,DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat.Brain Res,1995.676(2):p.398-403.
17.Nakajima,W.,et al.,Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat.J Neurosci,2000.20(21):p.7994-8004.
18.Northington,F.J.,et al.,Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis.J Neurosci,2001.21(6):p.1931-8.
19.Northington,F.J.,D.M.Ferriero,and L.J.Martin,Neurodegeneration in the thalamus following neonatal hypoxia-ischemia is programmed cell death.Dev Neurosci,2001.23(3):p.186-91.
20.Chen,J.,et al.,Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia.J Neurosci,1998.18(13):p.4914-28.
21.Zhang,X.,et al.,Intranuclear localization of apoptosis-inducing factor(AIF)and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite.J Neurochern,2002.82(1):p.181-91.
22.Daugas,E.,et al.,Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis.Faseb J,2000.14(5):p.729-39.
23.Cao,G.,et al.,Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation.J Cereb Blood Flow Metab,2003.23(10):p.1137-50.
24.Yin,W.,et al.,Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation.Stroke,2007.38(3):p.1017-24.
25.Yano,S.,et al.,Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus.J Cereb Blood Flow Metab,2001.21(4):p.351-60.
26.Cheng,Y.,et al.,Marked age-dependent neuroprotection by brain-derived neurotrophic factor against neonatal hypoxic-ischemic brain injury.Ann Neurol,1997.41(4):p.521-9.
27.Tomimatsu,T.,et al.,Long-term neuroprotective effects of hypothermia on neonatal hypoxic-ischemic brain injury in rats,assessed by auditory brainstem response.Pediatr Res,2003.53(1):p.57-61.
28.Adachi,M.,et al.,Combination effect of systemic hypothermia and caspase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats.Pediatr Res,2001.50(5):p.590-5.
29.Han,B.H.,et al.,Selective,reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury.J Biol Chem,2002.277(33):p.30128-36.
30.Hamrick,S.E.and D.M.Ferriero,The injury response in the term newborn brain:can we neuroprotect? Curr Opin Neurol,2003.16(2):p.147-54.
31.Yin,W.,et al.,TAT-mediated delivery of Bcl-xL protein is neuroprotective against neonatal hypoxic-ischemic brain injury via inhibition of caspases and AIF.Neurobiol Dis,2006.21(2):p.358-71.
32.Das,U.N.,Pyruvate is an endogenous anti-inflammatory and anti-oxidant molecule.Med Sci Monit,2006.12(5):p.RA79-84.
33.Salahudeen,A.K.,E.C.Clark,and K.A.Nath,Hydrogen peroxide-induced renal injury.A protective role for pyruvate in vitro and in vivo.J Clin Invest,1991.88(6):p.1886-93.
34.Bunger,R.,R.T.Mallet,and D.A.Hartman,Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart.Near-complete prevention of reperfusion contractile failure.Eur J Biochem,1989.180(1):p.221-33.
35.Cicalese,L.,et al.,Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine.Am J Surg,1996.171(1):p.97-100;discussion 100-1.
36.Tsung,A.,et al.,Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis.Transplantation,2005.79(2):p.196-204.
37.Sileri,P.,et al.,Pyruvate inhibits hepatic ischemia-reperfusion injury in rats.Transplantation,2001.72(1):p.27-30.
38.Gupta,S.K.,et al.,Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells.Ophthalmic Res,2002.34(1):p.23-8.
39.Lee,J.Y.,Y.H.Kim,and J.Y.Koh,Protection by pyruvate against transient forebrain ischemia in rats.J Neurosci,2001.21(20):p.RC171.
40.Slovin,EN.,et al.,Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock.Resuscitation,2001.50(1):p.109-15.
41.Mongan,P.D.,et al.,Intravenous pyruvate prolongs survival during hemorrhagic shock in swine.Am J Physiol,1999.277(6 Pt 2):p.H2253-63.
42.Sims,C.A.,et al.,Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.Crit Care Med,2001.29(8):p.1513-8.
43.Varma,S.D.,K.R.Hegde,and S.Kovtun,Oxidative damage to lens in culture:reversibility by pyruvate and ethylpyruvate.Ophthalmologica,2006.220(1):p.52-7.
44.Mulier,K.E.,et al.,Ringer's ethyl pyruvate in hemorrhagic shock and resuscitation does not improve early hemodynamics or tissue energetics.Shock,2005.23(3):p.248-52.
45.Sappington,P.L.,et al.,Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers.J Pharmacol Exp Ther,2003.304(1):p.464-76.
46.Tsai,B.M.,et al.,Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression.J Surg Res,2008.145(1):p.130-4.
47.Zingarelli,B.,Ethyl pyruvate:a simple solution? Crit Care Med,2004.32(7):p. 1603-4.
48.Yang,R.,et al.,Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock.Am J Physiol Gastrointest Liver Physiol,2002.283(1):p.G212-21.
49.Taylor,M.D.,et al.,Ethyl pyruvate enhances ATP levels,reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass.Heart Lung Circ,2005.14(1):p.25-31.
50.Tawadrous,Z.S.,R.L.Delude,and M.P.Fink,Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats.Shock,2002.17(6):p.473-7.
51.Venkataraman,R.,et al.,Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock.Shock,2002.18(6):p.507-12.
52.Song,M.,et al.,Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells.J Pharmacol Exp Ther,2004.308(1):p.307-16.
53.Miyaji,T.,et al.,Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice.Kidney Int,2003.64(5):p.1620-31.
54.Han,Y.,et al.,Ethyl pyruvate inhibits nuclear faetor-kappaB-dependent signaling by directly targeting p65.J Pharmacol Exp Ther,2005.312(3):p.1097-105.
55.Wang,H.,et al.,HMGB1 as a potential therapeutic target.Novartis Found Symp,2007.280:p.73-85;discussion 85-91,160-4.
56.Wang,L.Z.,W.C.Sun,and X.Z.Zhu,Ethyl pyruvate protects PC12 cells from dopamine-induced apoptosis.Eur J Pharmacol,2005.508(1-3):p.57-68.
57.Yang,R.,et al.,Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice.J Lab Clin Med,2003.142(5):p.322-31.
58.Cheng,B.Q.,et al.,Ethyl pyruvate improves survival and ameliorates distant organ injury in rats with severe acute pancreatitis.Pancreas,2007.35(3):p.256-61.
59.Fink,M.P.,Ethylpyruvate:a novel anti-inflammatory agent.J Intern Med,2007. 261(4):p.349-62.
60.Yang,R.,et al.,Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizingpancreatitis.Crit Care Med,2004.32(7):p.1453-9.
61.Fink,M.P.,Ethyl pyruvate:a novel treatment for sepsis.Novartis Found Symp,2007.280:p.147-56;discussion 156-64.
62.Kim,J.B.,et al.,Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain.Brain Res,2005.1060(1-2):p.188-92.
63.Cho,I.H.,et al.,Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus.J Neurosci Res,2006.84(7):p.1505-11.
64.Yu,Y.M.,et al.,Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window.Stroke,2005.36(10):p.2238-43.
65.Rice,J.E.,3rd,R.C.Vannucci,and J.B.Brierley,The influence of immaturity on hypoxic-ischemic brain damage in the rat.Ann Neurol,1981.9(2):p.131-41.
66.Levine,S.,Anoxic-ischemic encephalopathy in rats.Am J Pathol,1960.36:p.1-17.
67.Asoh,S.,et al.,Protection against ischemic brain injury by protein therapeutics.Proc Natl Acad Sci U S A,2002.99(26):p.17107-12.
68.Bona,E.,et al.,Protective effects of moderate hypothermia after neonatal hypoxia-ischemia:short- and long-term outcome.Pediatr Res,1998.43(6):p.738-45.
69.Lubics,A.,et al.,Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury.Behav Brain Res,2005.157(1):p.157-65.
70.Chen,J.,et al.,Early detection of DNA strand breaks in the brain after transient focal ischemia:implications for the role of DNA damage in apoptosis and neuronal cell death.J Neurochem,1997.69(1):p.232-45.
71.Hu,Y.,et al.,Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation.Proc Natl Acad Sci U S A,1998.95(8):p.4386-91.
72.Parsadanian,A.S.,et al.,Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons.J Neurosci,1998.18(3):p.1009-19.
73.Senftleben,U.and M.Karin,The IKK/NF-kappa B pathway.Crit Care Med,2002.30(1 Suppl):p.S18-26.
74.Milatovic,D.,et al.,Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum.J Neurochem,2003.87(6):p.1518-26.
75.Silverstein,F.S.,B.Naik,and J.Simpson,Hypoxia-ischemia stimulates hippocampal glutamate efflux in perinatal rat brain:an in vivo microdialysis study.Pediatr Res,1991.30(6):p.587-90.
76.Gordon,K.E.,et al.,Effects of perinatal stroke on striatal amino acid efflux in rats studied with in vivo microdialysis.Stroke,1991.22(7):p.928-32.
77.Thoresen,M.and J.Wyatt,Keeping a cool head,post-hypoxic hypothermia--an old idea revisited.Acta Paediatr,1997.86(10):p.1029-33.
78.Vannucci,R.C.,et al.,Measuring the accentuation of the brain damage that arises from perinatal cerebral hypoxia-ischemia.Biol Neonate,1997.72(3):p.187-91.
79.Fernandez-Gomez,F.J.,et al.,Pyruvate protects cerebellar granular cells from 6-hydroxydopamine-induced cytotoxicity by activating the Akt signaling pathway and increasing glutathione peroxidase expression.Neurobiol Dis,2006.24(2):p.296-307.
80.Ulloa,L.,et al.,Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci U S A,2002.99(19):p.12351-6.
1.Mitchell RFink,MD,FCCM.Ethyl pyruvate:A novel anti-inflammatory agent.Crit.Care.Med.31(1 suppl):s51-s56(2003)
2.Salahudeen AK,Clark EC,Nath KA:Hydrogenperoxide-induced renal injury:A protectiverole for pyruvate in vitro and in vivo.J Clin Invest 1991;88:1886-1893
3.Bunger R,Mallet RT,Hartman DA:Pyruvate enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart:Near-complete prevention of reperfusion contractile failure.Eur J Bioehem 1989;180:221-233
4.Cicalese L,Lee K,Schraut W,et al:Pyruvate prevents ischemia-reperfusion mucosal injury of rat small intestine.Am J Surg 1999;171:97-100
5.Sileri P,Schena S,Morini S,et al:Pyruvate inhibits hepatic ischemia-reperfusion injury in rats.Transplantation 2001;72:27-30
6.Gupta SK,Mohanty I,Trivedi D,et al:Pyruvate inhibits galactosemic changes in cultured cat lens epithelial cells.Ophthalmic Res 2002;34:23-28
7.Lee JY,Kim YH,Koh JY:Protection by pyruvate against transient forebrain ischemia in rats.J Neurosci 2002;21:1-6
8.Slovin PN,Huang CJ,Cade JR,et al:Sodium pyruvate is better than sodium chloride as a resuscitation solution in a rodent model of profound hemorrhagic shock.Resuscitation 2001;50:109-115
9.Mongan PD,Capacchione J,Fontana JL,et al:Pyruvate improves cerebral metabolism during hemorrhagic shock.Am J Physio12001;281:H854-H864
10.Mongan PD,Fontana JL,Chen R,et al:Intravenous pyruvate prolongs survival during hemorrhagic shock in swine.Am J Physiol 1999;277:H2253-H2263
11.Sims CA,Wattanasirichaigoon S,Menconi MJ,et al:Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.Crit Care Med 2001;29:1513-1518
12.Varma SD,Devamanoharan PS,Ali AH:Prevention of intracellular oxidative stress to lens by pyruvate and its ester.Free Rad Res 1998;28:131-135
13.Tawadrous ZS,Delude RL,Fink MP:Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats.Shock 2002;17:473-477
14.Yang R,Gallo DJ,Baust JJ,et al:Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock.Am J Physiol Gastrointest Liver Physio12002;283:G212-G22
15.Venkataraman R,Kellum JA,Song M,et al:Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharideinduced shock.Shock In Press
16.Ulloa L,Ochani M,Yang H,et al:Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci USA 2002;99:12351-12356
17.Wang,L.Z.,W.C.Sun,and X.Z.Zhu,Ethyl pyruvate protects PC12 cells from dopamine-induced apoptosis.Eur J Pharmacol,2005.508(1-3):p.57-68.
18.Cho,I.H.,et al.,Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus.J Neurosci Res,2006.84(7):p.1505-11.
19.金晶:NF.KB的研究进展.国外医学药学分册2000;27(3):131-137
20.Schoonbroodt S,Ferreira V,Best-Belpomme M,et al:Crucial role of the amino-terminal tyrosine residue 42 and the carboxylterminal PEST domain of IkBa in NF-kB activation by oxidative stress. J Immunol 2000; 164:4292-4300
21.Yusheng Han,Mitchell et al: ethyle pyruvate inhibits NF-κB-dependent signaling by directly targeting p65. JPET Fast Forward; Published on November 3,2004