Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window.
OBJECTIVE
Ethyl pyruvate (EP) is a pyruvate derivative that has been reported recently to prevent lethality in mice with established lethal sepsis and systemic inflammation. In this study, we examined the neuroprotective effect of EP in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO).


METHODS
Male Sprague-Dawley rats were subjected to 1 hour of MCAO, and EP was administered at various time points before or after MCAO. The changes in the brain infarction, neurological deficits, microglia activation, and proinflammatory cytokine expression were evaluated. BV2 microglial cells were also used to access the anti-inflammatory effect of EP.


RESULTS
The administration of EP intraperitoneally at 30 minutes before or at 4 or 12 hours after MCAO reduced the infarct volume to 10.3+/-3.4% (n=6; P<0.05), 21.5+/-2.7% (n=6; P<0.05), and 44.3+/-4.0% (n=6; P<0.05), respectively, of that of the control group. The significant reduction in infarct volume was accompanied by the suppression of the clinical manifestations associated with cerebral ischemia, including motor impairment and neurological deficits, microglial activation, and proinflammatory cytokine expression. The neuroprotective effect of EP was yet evident when it was administered as late as 24 hours after MCAO/reperfusion (76.5+/-4.70%; n=6; P<0.05). EP suppressed lipopolysaccharide induced activation of BV2 cells, as was evidenced by a reduction in NO release and the accompanying induction of proinflammatory cytokines.


CONCLUSIONS
These results suggest that EP affords the strong protection of the delayed cerebral ischemic injury with a wide therapeutic window.
Yu
Young-Mi
YM
Department of Anatomy, Inha University School of Medicine, Inchon, 400-712, Republic of Korea.
Kim
Jung-Bin
JB
Lee
Kang-Woo
KW
Kim
Seong Yun
SY
Han
Pyung-Lim
PL
Lee
Ja-Kyeong
JK
D000818:Animals; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy*; D002545:Brain Ischemia / Q000473:pathology*; D004396:Coloring Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D007249:Inflammation / Q000628:therapy; D007511:Ischemia; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009483:Neuropsychological Tests; D009569:Nitric Oxide / Q000378:metabolism; D011773:Pyruvates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000628:therapy; D013778:Tetrazolium Salts / Q000494:pharmacology; D013997:Time Factors
D004396:Coloring Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D011773:Pyruvates; D013778:Tetrazolium Salts; C046522:ethyl pyruvate; D009569:Nitric Oxide; C009591:triphenyltetrazolium