Soustiel Jean F, Zaaroor Menashe, Vlodavsky Eugene, Veenman Leo, Weizman Abraham, Gavish Moshe
Acute Brain Injury Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Exp Neurol. 2008 Dec;214(2):201-8. doi: 10.1016/j.expneurol.2008.08.008. Epub 2008 Aug 27.
The 18 kDa translocator protein (TSPO) is a protein complex located at the outer mitochondrial membrane and interacting with the mitochondrial permeability transition pore (mPTP), indicating its involvement in the control of mPTP opening. We intended to explore the effect of TSPO ligands, PK 11195 and Ro5-4864 on apoptosis in a rat model of cortical injury. Sprague-Dawley rats received a daily intraperitoneal injection of dimethylsulfoxide (vehicle), PK 11195, or Ro5-4864, starting 2 days prior the injury and a third injection after the injury. At 6 weeks, immunohistochemistry analysis showed that Ro5-4864 resulted in a significant increase in the number of surviving neurons and in the density of the neurofilament network in the perilesional cortex in comparison with animals of the vehicle and PK 11195 groups. In tissue samples dissected from the injured area, Ro5-4864 caused a significant reduction in activation of caspases 3 and 9 but not of caspase 8 in comparison with the vehicle and PK 11195 groups. In addition, measurements of transmembrane mitochondrial potential of mitochondria (Deltapsi(M)) isolated from normal rat brain showed that loss of Deltapsi(M) induced by recombinant Bax could be significantly reduced by Ro5-4864 in a concentration-dependent manner. Our findings indicate that the neuroprotective effect shown by Ro5-4864 in the present model of brain injury involves the mitochondrial pathway of apoptosis modulation of mPTP.
18 kDa转位蛋白（TSPO）是一种位于线粒体外膜并与线粒体通透性转换孔（mPTP）相互作用的蛋白质复合物，表明其参与mPTP开放的调控。我们旨在探讨TSPO配体PK 11195和Ro5-4864对皮质损伤大鼠模型中细胞凋亡的影响。从损伤前2天开始，Sprague-Dawley大鼠每日腹腔注射二甲基亚砜（溶媒）、PK 11195或Ro5-4864，损伤后再注射一次。6周时，免疫组织化学分析显示，与溶媒组和PK 11195组动物相比，Ro5-4864导致损伤周围皮质中存活神经元数量显著增加，神经丝网络密度增加。在从损伤区域分离的组织样本中，与溶媒组和PK 11195组相比，Ro5-4864导致半胱天冬酶3和9的激活显著降低，但半胱天冬酶8的激活没有降低。此外，对从正常大鼠脑分离的线粒体跨膜电位（ΔψM）的测量表明，Ro5-4864可以浓度依赖性方式显著降低重组Bax诱导的ΔψM丧失。我们的研究结果表明，Ro5-4864在本脑损伤模型中显示的神经保护作用涉及mPTP凋亡调节的线粒体途径。
