Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice.
Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice.
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靛玉红衍生物 7-Bromoindirubin-3-Oxime (7Bio) 可减轻 A beta 寡聚物引起的小鼠认知障碍
DOI：
10.3389/fnmol.2017.00393
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发表时间：
2017
影响因子：
4.8
通讯作者：
Cui W
中科院分区：
文献类型：
--
作者：
Chen L;Huang C;Shentu J;Wang M;Yan S;Zhou F;Zhang Z;Wang C;Han Y;Wang Q;Cui W
蓝宝石是从含有蓝宝石染料的植物中提取的天然生物碱。靛玉红可以抑制多种激酶，并可能用于治疗慢性粒细胞白血病、癌症和神经退行性疾病。7-溴吲哚红-3-肟(7Bio)是一种由吲哚红-3-肟衍生而来的靛玉红衍生物，对阿尔茨海默病(AD)的两个药理靶点--细胞周期蛋白依赖性激酶-5(CDK-5)和糖原合成酶-3-β(GSK-3-β)具有抑制作用。在本研究中，我们发现2.3-2 3.3μg/kg 7Bio有效地阻止了A-淀粉样蛋白(β-β)寡聚体引起的小鼠空间认知和再认障碍，而不影响体重和运动功能。此外，7Bio还能有效抑制Aβ寡聚体诱导的白介素6和肿瘤坏死因子α的表达。此外，7Bio显著阻止了Aβ寡聚体处理的小鼠突触前和突触后蛋白的生物标志物突触素-1和突触-95的表达下降。7Bio处理组小鼠海马区高磷酸化tau蛋白、胶质纤维酸性蛋白和CD45阳性染色的平均光密度(OD)均显著低于Aβ寡聚体处理组。此外，Western blotting分析表明，7Bio可减弱Aβ寡聚体降低的pSer9-GSK3β的表达。结果提示，7Bio能有效抑制Aβ寡聚体诱导的神经炎症、突触损伤、tau蛋白过度磷酸化以及星形胶质细胞和小胶质细胞的激活，这可能是7Bio的神经保护作用之一。基于这些发现，我们预计7Bio可能被开发为一种新型的抗AD先导化合物。
Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3–23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.
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