Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain.
Ethyl pyruvate (EP) is a pyruvate derivative, and has recently been reported to prevent lethality in mice with established lethal sepsis and systemic inflammation. In a previous study, we reported that EP has a neuroprotective effect in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO), in which it was found to be effective when injected as late as 12 h after MCAO/reperfusion. In the present study, we show that therapeutic window of pyruvate in this MCAO animal model is limited to 1 h (30 min before and 30 min after MCAO). Moreover, both pyruvate and EP have a neuroprotective effect during oxygen-glucose deprivation (OGD) or H2O2 challenge in primary cortical culture. In contrast, EP suppressed the LPS-induced activation of primary microglia in culture, but pyruvate did not. The suppression of microglia activation was evidenced by a reduction in nitric oxide release and by a proinflammatory factor induction in primary microglia culture, which were accompanied by the repression of nuclear factor-kappaB activation. These results suggest that EP has a strong protective effect and a wide therapeutic window, and that this protective effect of EP is related to its anti-inflammatory action.
Kim
Jung-Bin
JB
Department of Anatomy, Inha University School of Medicine, 7-241 Shinheung-dong, Jung-Gu, Inchon 400-712, Republic of Korea.
Yu
Young-Mi
YM
Kim
Seung-Woo
SW
Lee
Ja-Kyeong
JK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005947:Glucose / Q000172:deficiency; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats
D016328:NF-kappa B; D018696:Neuroprotective Agents; D016877:Oxidants; D011773:Pyruvates; C046522:ethyl pyruvate; D006861:Hydrogen Peroxide; D005947:Glucose