Chen Yicong, Veenman Leo, Singh Sukhdev, Ouyang Fubing, Liang Jiahui, Huang Weixian, Marek Ilan, Zeng Jinsheng, Gavish Moshe
From the Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Y.C., F.O., J.L., W.H., J.Z.); Department of Neuroscience, Israel Institute of Technology, Haifa, Israel (L.V., M.G.); and Department of Organic Chemistry, Israel Institute of Technology, Haifa (S.S., I.M.).
Stroke. 2017 Dec;48(12):3366-3374. doi: 10.1161/STROKEAHA.117.019439. Epub 2017 Nov 16.
Focal cortical infarction causes neuronal apoptosis in the ipsilateral nonischemic thalamus and hippocampus, which is potentially associated with poststroke cognitive deficits. TSPO (translocator protein) is critical in regulating mitochondrial apoptosis pathways. We examined the effects of the novel TSPO ligand 2-(2-chlorophenyl) quinazolin-4-yl dimethylcarbamate (2-Cl-MGV-1) on poststroke cognitive deficits, neuronal mitochondrial apoptosis, and secondary damage in the ipsilateral thalamus and hippocampus after cortical infarction.
One hundred fourteen hypertensive rats underwent successful distal middle cerebral artery occlusion (n=76) or sham procedures (n=38). 2-Cl-MGV-1 or dimethyl sulfoxide as vehicle was administrated 2 hours after distal middle cerebral artery occlusion and then for 6 or 13 days (n=19 per group). Spatial learning and memory were tested using the Morris water maze. Secondary degeneration and mitochondrial apoptosis in the thalamus and hippocampus were assessed using Nissl staining, immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling, JC-1 staining, and immunoblotting 7 and 14 days after surgery.
Infarct volumes did not significantly differ between the vehicle and 2-Cl-MGV-1 groups. There were more neurons and fewer glia in the ipsilateral thalamus and hippocampus in the vehicle groups than in the sham-operated group 7 and 14 days post-distal middle cerebral artery occlusion. 2-Cl-MGV-1 significantly ameliorated spatial cognitive impairment and decreased neuronal death and glial activation when compared with vehicle treatment (<0.05). The collapse of mitochondrial transmembrane potential and cytoplasmic release of apoptosis-inducing factors and cytochrome was prevented within the thalamus. Caspase cleavage and the numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling or Nissl atrophic cells were reduced within the thalamus and hippocampus. This was accompanied by upregulation of B-cell lymphoma 2 and downregulation of Bax (<0.05).
2-Cl-MGV-1 reduces neuronal apoptosis via mitochondrial-dependent pathways and attenuates secondary damage in the nonischemic thalamus and hippocampus, potentially contributing to ameliorated cognitive deficits after cortical infarction.
局灶性皮质梗死可导致同侧非缺血性丘脑和海马神经元凋亡，这可能与卒中后认知功能障碍有关。转位蛋白（TSPO）在调节线粒体凋亡途径中起关键作用。我们研究了新型TSPO配体2-（2-氯苯基）喹唑啉-4-基二甲基氨基甲酸酯（2-Cl-MGV-1）对皮质梗死后卒中后认知功能障碍、神经元线粒体凋亡以及同侧丘脑和海马继发性损伤的影响。
114只高血压大鼠成功进行大脑中动脉远端闭塞术（n = 76）或假手术（n = 38）。在大脑中动脉远端闭塞后2小时给予2-Cl-MGV-1或作为溶剂的二甲基亚砜，然后持续给药6天或13天（每组n = 19）。使用莫里斯水迷宫测试空间学习和记忆能力。在术后7天和14天，采用尼氏染色、免疫组织化学、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记、JC-1染色和免疫印迹法评估丘脑和海马的继发性变性和线粒体凋亡情况。
溶剂组和2-Cl-MGV-1组的梗死体积无显著差异。大脑中动脉远端闭塞术后7天和14天，溶剂组同侧丘脑和海马中的神经元比假手术组更多，胶质细胞更少。与溶剂治疗相比，2-Cl-MGV-1显著改善了空间认知障碍，减少了神经元死亡和胶质细胞激活（P<0.05）。在丘脑中，线粒体跨膜电位的崩溃以及凋亡诱导因子和细胞色素c的细胞质释放得到了预防。丘脑中半胱天冬酶的裂解以及末端脱氧核苷酸转移酶介导的dUTP缺口末端标记或尼氏萎缩细胞数量减少。同时伴有B细胞淋巴瘤2上调和Bax下调（P<0.05）。
2-Cl-MGV-1通过线粒体依赖性途径减少神经元凋亡，并减轻非缺血性丘脑和海马的继发性损伤，这可能有助于改善皮质梗死后的认知功能障碍。
