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-kappa B 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. (c) 2005 Elsevier B.V. All rights reserved.