Liu Qin, Zhang Jinqiang, Xiao Chenghong, Su Dapeng, Li Liangyuan, Yang Changgui, Zhao Zhihuang, Jiang Weike, You Zili, Zhou Tao
Resource Institute for Chinese & Ethnic Materia Medica, Guizhou University of Traditional Chinese Medicine, Guiyang, China.
School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
Front Pharmacol. 2022 Aug 30;13:927419. doi: 10.3389/fphar.2022.927419. eCollection 2022.
Given the ability of akebia saponin D (ASD) to protect various types of stem cells, in the present study, we hypothesized that ASD could promote the proliferation, differentiation, and survival of neural stem/precursor cells (NSPCs), even in a microglia-mediated inflammatory environment, thereby mitigating inflammation-related neuropsychopathology. We established a mouse model of chronic neuroinflammation by exposing animals to low-dose lipopolysaccharide (LPS, 0.25 mg/kg/d) for 14 days. The results showed that chronic exposure to LPS strikingly reduced hippocampal levels of PI3K and pAkt and neurogenesis in mice. In the presen of a microglia-mediated inflammatory niche, the PI3K-Akt signaling in cultured NSPCs was inhibited, promoting their apoptosis and differentiation into astrocytes, while decreasing neurogenesis. Conversely, ASD strongly increased the levels of PI3K and pAkt and stimulated NSPC proliferation, survival and neuronal differentiation in the microglia-mediated inflammatory niche and . ASD also restored the synaptic function of hippocampal neurons and ameliorated depressive- and anxiety-like behaviors and cognitive impairment in mice chronically exposed to LPS. The results from network pharmacology analysis showed that the PI3K-AKT pathway is one of the targets of ASD to against major depressive disorder (MDD), anxiety and Alzheimer's disease (AD). And the results from molecular docking based on computer modeling showed that ASD is bound to the interaction interface of the PI3K and AKT. The PI3K-Akt inhibitor LY294002 blocked the therapeutic effects of ASD and . These results suggested that ASD protects NSPCs from the microglia-mediated inflammatory niche, promoting their proliferation, survival and neuronal differentiation, as well as ameliorating depressive- and anxiety-like behaviors and cognitive impairment by activating the PI3K-AKT pathway. Our work suggests the potential of ASD for treating Alzheimer's disease, depression and other cognitive disorders involving impaired neurogenesis by microglia-mediated inflammation.
鉴于木通皂苷D（ASD）具有保护多种类型干细胞的能力，在本研究中，我们推测ASD可以促进神经干/前体细胞（NSPCs）的增殖、分化和存活，即使在小胶质细胞介导的炎症环境中也是如此，从而减轻与炎症相关的神经精神病理学症状。我们通过给动物低剂量脂多糖（LPS，0.25mg/kg/d）连续处理14天，建立了慢性神经炎症小鼠模型。结果表明，慢性暴露于LPS显著降低了小鼠海马中PI3K和pAkt的水平以及神经发生。在小胶质细胞介导的炎症微环境中，培养的NSPCs中的PI3K-Akt信号传导受到抑制，促进了它们的凋亡并分化为星形胶质细胞，同时减少了神经发生。相反，ASD强烈增加了PI3K和pAkt的水平，并在小胶质细胞介导的炎症微环境中刺激了NSPCs的增殖、存活和神经元分化。ASD还恢复了海马神经元的突触功能，并改善了长期暴露于LPS的小鼠的抑郁样和焦虑样行为以及认知障碍。网络药理学分析结果表明，PI3K-AKT通路是ASD对抗重度抑郁症（MDD）、焦虑症和阿尔茨海默病（AD）的靶点之一。基于计算机模拟的分子对接结果表明，ASD与PI3K和AKT的相互作用界面结合。PI3K-Akt抑制剂LY294002阻断了ASD的治疗效果。这些结果表明，ASD保护NSPCs免受小胶质细胞介导的炎症微环境的影响，通过激活PI3K-AKT通路促进它们的增殖、存活和神经元分化，以及改善抑郁样和焦虑样行为和认知障碍。我们的工作表明ASD在治疗由小胶质细胞介导的炎症导致神经发生受损的阿尔茨海默病、抑郁症和其他认知障碍方面具有潜力。
