2-(3′,5′-DIMETHOXYBENZYLIDENE) CYCLOPENTANONE, A NOVEL SYNTHETIC SMALL-MOLECULE COMPOUND, PROVIDES NEUROPROTECTIVE EFFECTS AGAINST ISCHEMIC STROKE
2-(3′,5′-DIMETHOXYBENZYLIDENE) CYCLOPENTANONE, A NOVEL SYNTHETIC SMALL-MOLECULE COMPOUND, PROVIDES NEUROPROTECTIVE EFFECTS AGAINST ISCHEMIC STROKE
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DOI：
10.1016/j.neuroscience.2015.11.052
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发表时间：
2016-03-01
期刊：
影响因子：
3.3
通讯作者：
Ao, G. Z.
中科院分区：
文献类型：
--
作者：
Gu, W. W.;Lu, S. Q.;Ao, G. Z.
2-(3',5'-二甲氧基亚苄基)环戊酮(DMBC)是我们课题组合成的一种新型小分子化合物。在这里，我们发现，在永久性大脑中动脉闭塞（pMCAO）的大鼠模型中，缺血后1小时腹腔注射（ip）DMBC可减少梗塞体积，改善神经功能缺损，并增加缺血皮质中微管相关蛋白2（MAP 2）和胶质纤维酸性蛋白（GFAP）的蛋白水平。即使在缺血后 6 小时给药，DMBC 后处理仍能产生神经保护作用。在氧糖剥夺 (OGD) 诱导的星形胶质细胞或 HT22 细胞损伤中，DMBC 治疗减少了 OGD 诱导的乳酸脱氢酶 (LDH) 渗漏，并增加了星形胶质细胞中的 GFAP 水平。此外，Annexin-V-Fluos 染色分析表明，DMBC 治疗可减弱 OGD 诱导的星形胶质细胞凋亡和坏死。 Western blotting 分析显示，DMBC 治疗可抑制缺血或 OGD 诱导的缺血皮质、星形胶质细胞或 HT22 细胞中活性组织蛋白酶 B 的增加。免疫荧光分析表明，DMBC 治疗可阻断缺血或 OGD 诱导的组织蛋白酶 B 从溶酶体释放到缺血皮质或星形胶质细胞或 HT22 细胞的细胞质中。综上所述，我们的结果表明 DMBC 可以提供针对脑缺血的神经保护作用，并延长治疗窗，其机制可能与抑制组织蛋白酶 B 激活有关。 (C) 2015 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
2-(3',5'-Dimethoxybenzylidene) cyclopentanone (DMBC) is a novel small-molecule compound synthesized by our group. Here, we found that in rat models of permanent middle cerebral artery occlusion (pMCAO), intraperitoneal injection (ip) of DMBC at 1 h after ischemia reduced infarct volume, improved neurological deficits and increased the protein levels of microtubule-associated protein 2 (MAP 2) and glial fibrillary acid protein (GFAP) in the ischemic cortex. Post-treatment of DMBC still produced neuroprotective effects even when administered at 6 h after ischemia. In the oxygen-glucose deprivation (OGD)-induced astrocytes or HT22 cell injury, DMBC treatment decreased the OGD-induced lactate dehydrogenase (LDH) leakage and increased the GFAP levels in astrocytes. In addition, Annexin-V-Fluos staining analysis revealed that DMBC treatment attenuated both OGD-induced apoptosis and necrosis in astrocytes. Western blotting analysis showed DMBC treatment inhibited the ischemia or OGD-induced increases in active cathepsin B in the ischemic cortex or in astrocytes or HT22 cells. Immunofluorescence analysis demonstrated that DMBC treatment blocked the ischemia or OGD-induced release of cathepsin B from the lysosomes into the cytoplasm in the ischemic cortex or in astrocytes or HT22 cells. Taken together, our results indicate that DMBC can offer neuroprotective effects against cerebral ischemia with an extended therapeutic window and its mechanism might be associated with inhibition of the cathepsin B activation. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.