Yan Tao, Venkat Poornima, Chopp Michael, Zacharek Alex, Yu Peng, Ning Ruizhuo, Qiao Xiaoxi, Kelley Mark R, Chen Jieli
1Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
2Department of Neurology, Henry Ford hospital, Detroit, MI, USA.
Aging Dis. 2018 Jun 1;9(3):453-466. doi: 10.14336/AD.2017.1130. eCollection 2018 Jun.
APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.
APX3330是一种APE1/Ref-1氧化还原活性的选择性抑制剂。在本研究中，我们探究了APX3330治疗1型糖尿病（T1DM）中风大鼠的治疗效果及潜在机制。成年雄性Wistar大鼠被诱导患T1DM，然后进行短暂性大脑中动脉闭塞（MCAo），并在MCAo后24小时开始用PBS或APX3330（10mg/kg，灌胃）治疗，每天一次，持续14天。在MCAo后14天处死大鼠，并进行血脑屏障（BBB）通透性、缺血性病变体积、免疫组织化学、细胞死亡检测、蛋白质印迹、实时PCR和血管生成ELISA阵列检测。与PBS治疗相比，APX3330治疗T1DM大鼠中风可显著改善神经功能结局，减小病变体积，改善BBB完整性，降低总血管密度和VEGF表达，同时显著增加缺血边界区（IBZ）的动脉密度。APX3330可显著增加T1DM中风大鼠IBZ中的髓磷脂密度、少突胶质细胞数量、少突胶质前体细胞数量、突触蛋白表达，并诱导M2巨噬细胞极化。与PBS治疗相比，APX3330治疗可显著降低T1DM中风大鼠缺血脑中1型纤溶酶原激活物抑制剂（PAI-1）、单核细胞趋化蛋白-1和基质金属蛋白酶9（MMP9）以及晚期糖基化终产物受体的表达。与未处理的对照细胞相比，APX3330治疗可显著降低高糖和氧糖剥夺处理的原代皮质神经元中的细胞死亡以及MMP9和PAI-1基因表达。APX3330治疗可增加缺血脑中的M2巨噬细胞极化，降低炎症因子表达，并促进T1DM大鼠中风后的神经保护和神经修复作用。
