Klinik für Neurologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Neurochem Res. 2010 Sep;35(9):1391-401. doi: 10.1007/s11064-010-0197-0. Epub 2010 Jun 1.
The antioxidant and inhibitor of nuclear factor kappaB pyrrolidine dithiocarbamate (PDTC) potently reduces infarct size in various experimental stroke models. In addition, it has been shown to have a favourable safety profile in humans. In this study, we further investigated the mechanistic actions of PDTC on cerebral microvascular endothelial cells as main components of the blood-brain barrier. We propose activation of p38 MAPK by PDTC as an additional protective mechanism. C57/BL6 mice were subjected to transient MCAO for 2 h and treated with PDTC (100 mg/kg) or vehicle i.p. before reperfusion. Infarct size was determined after 24 h. Apoptosis was induced in a cerebral microvascular endothelial cell line and the effect of pretreatment with PDTC and its dependency on p38 MAPK activity was assayed. PDTC administered 2 h after MCAO reduced infarct size by 61% (P < 0.05) and reduces the apoptotic death rate in vivo. In vitro, PDTC reduces the apoptotic death rate of bEnd.3 cells. p38 MAPK was activated by PDTC and its inhibition abrogated the protective effect of PDTC. PDTC reduces infarct size after stroke with a reasonable time window and decreases apoptotic cell death in vivo and in vitro. The attenuation of apoptotic cell death in brain microvascular endothelial cells is dependent on p38 MAPK activity.
抗氧化剂和核因子 kappaB 抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）可强烈减少各种实验性中风模型中的梗死面积。此外，它已被证明在人类中具有良好的安全性。在这项研究中，我们进一步研究了 PDTC 对脑微血管内皮细胞（血脑屏障的主要组成部分）的机制作用。我们提出 PDTC 通过激活 p38 MAPK 作为一种额外的保护机制。将 C57/BL6 小鼠进行短暂性 MCAO 2 小时，然后在再灌注前通过腹腔内给予 PDTC（100mg/kg）或载体处理。在 24 小时后测定梗死面积。在脑微血管内皮细胞系中诱导细胞凋亡，并测定 PDTC 预处理及其对 p38 MAPK 活性的依赖性的作用。MCAO 后 2 小时给予 PDTC 可使梗死面积减少 61%（P<0.05），并降低体内的细胞凋亡率。在体外，PDTC 降低 bEnd.3 细胞的细胞凋亡率。PDTC 激活了 p38 MAPK，其抑制作用消除了 PDTC 的保护作用。PDTC 可在合理的时间窗口内减少中风后的梗死面积，并降低体内和体外的细胞凋亡。脑微血管内皮细胞中凋亡细胞死亡的减少依赖于 p38 MAPK 活性。
