ETHYL PYRUVATE 의 신경계 보호 기전

초록

Ethyl pyruvate (EP) is a pyruvate derivative, which has been recently reported 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). Male Sprauge-Dawley rats were subjected to 1 hr 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. The administration of EP intraperitoneally at 30 min before, or at 4 hrs or 12 hrs 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 hrs after the MCAO/reperfusion (76.5±4.70%, n=6, p< 0.05). EP suppressed LPS-induced activation of BV2 cells, as was evidenced by a reduction in nitric oxide release and the accompanying induction of proinflammatory cytokines. These results suggest that EP affords the strong protection of the delayed cerebral ischemic injury with a wide therapeutic window.