Department of Anatomy, Center for Advanced Medical Education (BK21 Project), Inha University School of Medicine, 7-241 Shinheung-Dong, Jung-Gu, Inchon, 400-712, Republic of Korea.
Neurotox Res. 2010 Jan;17(1):39-49. doi: 10.1007/s12640-009-9075-4. Epub 2009 Jul 28.
Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule in various pathological conditions, which include sepsis or hemorrhagic shock. Recently, we showed that ethyl pyruvate has a neuroprotective effect in the postischemic brain and also in KA-induced pathogenesis in the brain. In this study, we examined whether aspirin augments neuroprotective effect of ethyl pyruvate in transient focal ischemia model by complementing the neuroprotective effects of ethyl pyruvate. Although, most of neuroprotective effect of aspirin has been attributed to the anti-platelet action, aspirin also has direct neuroprotective effects, including NF-kappaB inhibition. Ethyl pyruvate dose-dependently suppressed infarct formation in the postischemic brain, wherein intravenous administration of 5 mg/kg ethyl pyruvate 30 min after the occlusion reduced infarct volume to 34.5 +/- 15.5% (n = 6, P < 0.01) of that of the untreated control. In combination with aspirin (5 mg/kg, i.v.), the neuroprotective effect was enhanced, resulting in 16.0 +/- 5.9% (n = 6, P < 0.01) infarct volume. The time window for synergistic neuroprotection by ethyl pyruvate and aspirin extended to 9 h post-MCAO. The synergistic reduction in infarct volume was accompanied by suppression of the clinical manifestations associated with cerebral ischemia including motor impairment and neurological deficits. Inflammatory processes including microglial activation and proinflammatory cytokine expression were notably suppressed by the combination treatment in the postischemic brain and in primary microglia cultures, wherein ethyl pyruvate and aspirin modulate NF-kappaB signaling differentially. Aspirin interferes with IkappaB phosphorylation and degradation in the cytoplasm, possibly by specifically inhibiting IkappaB kinase-beta, whereas, the effect of ethyl pyruvate seems to occur in the nucleus, where it may interfere with the binding of NF-kappaB to responsive promoter elements in the target genes. Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn(2+) treatment or oxygen-glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-kappaB signaling pathway.
丙酮酸乙酯（EP）是丙酮酸的一种简单的脂族酯，已被证明在各种病理条件下具有抗炎作用，包括败血症或失血性休克。最近，我们发现丙酮酸乙酯在缺血后的大脑中具有神经保护作用，并且在大脑中的 KA 诱导发病中也具有神经保护作用。在这项研究中，我们检查了阿司匹林是否通过补充丙酮酸乙酯的神经保护作用来增强其在短暂性局灶性缺血模型中的神经保护作用。尽管阿司匹林的大部分神经保护作用归因于抗血小板作用，但阿司匹林也具有直接的神经保护作用，包括 NF-κB 抑制。丙酮酸乙酯剂量依赖性地抑制缺血后大脑中的梗死形成，其中在闭塞后 30 分钟静脉内给予 5mg/kg 丙酮酸乙酯可将梗死体积减少至未治疗对照组的 34.5±15.5%（n=6，P<0.01）。与阿司匹林（5mg/kg，静脉内）联合使用时，神经保护作用增强，导致梗死体积减少 16.0±5.9%（n=6，P<0.01）。丙酮酸乙酯和阿司匹林协同神经保护的时间窗口扩展至 MCAO 后 9 小时。协同减少梗死体积伴随着抑制与脑缺血相关的临床表现，包括运动障碍和神经功能缺损。联合治疗在缺血后大脑和原代小胶质细胞培养物中显著抑制炎症过程，包括小胶质细胞活化和促炎细胞因子表达，其中丙酮酸乙酯和阿司匹林通过不同的方式调节 NF-κB 信号。阿司匹林通过特异性抑制 IκB 激酶-β来干扰细胞质中 IκB 的磷酸化和降解，而丙酮酸乙酯的作用似乎发生在核内，在核内它可能干扰 NF-κB 与靶基因中响应启动子元件的结合。在 NMDA 或 Zn2+处理或氧葡萄糖剥夺后，在原代皮质培养物中也观察到类似的神经保护作用增强。总之，这些结果表明，在缺血后的大脑中，丙酮酸乙酯和阿司匹林的联合治疗具有广泛的治疗窗口，可提供协同的神经保护作用，部分原因是通过对 NF-κB 信号通路的差异调节。
