Protection By Ethyl Pyruvate Against Hypoxic-Ischemic Brain Injury In Neonatal Rats

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.