Liu Zhenhong, Qin Gaofeng, Mana Lulu, Huang Shuaiyang, Wang Yahan, Wang Pengwen
Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.
Key Laboratory of Pharmacology of Dongzhimen Hospital (BUCM), State Administration of Traditional Chinese Medicine, Beijing, China.
Evid Based Complement Alternat Med. 2020 Jul 24;2020:4527283. doi: 10.1155/2020/4527283. eCollection 2020.
White matter degeneration and demyelination are nonnegligible pathological manifestations of Alzheimer's disease (AD). The damage of myelin sheath consisting of oligodendrocytes is the basis of AD's unique early lesions. Shenzhiling oral liquid (SZL) was the effective Chinese herbal compound approved by the Food and Drug Administration (FDA) for the treatment of AD in China, which plays the exact therapeutic role in clinical AD patients. However, its molecular mechanism remains unclear to date. For this purpose, an in vitro mode of streptozotocin- (STZ-) induced rat oligodendrocyte OLN-93 cell injury was established to mimic the pathological changes of myelin sheath of AD and investigate the mechanism of SZL protecting injured OLN-93 cell. The results showed that STZ can decrease cell viability and downregulate the activity of PI3K/Akt-mTOR signalling pathway and the expression of myelin sheath-related proteins (MBP, MOG, and PLP) in OLN-93 cells. Both SZL-medicated serum and donepezil (positive control) can protect cells from STZ-caused damage. SZL-medicated serum increased OLN-93 cell viability in a dose- and time-dependent manner and enhanced the activity of PI3K/Akt-mTOR signalling pathway. The inhibitor of PI3K (LY294002) inhibited the protective effect of SZL-medicated serum on the STZ-injured OLN-93 cells. Furthermore, rapamycin, the inhibitor of mTOR, inhibited the promotion of cell viability and upregulation of p-mTOR and MBP caused by SZL-medicated serum. In conclusion, our data indicate that SZL plays its therapeutic role on AD by promoting PI3K/Akt-mTOR signalling pathway of oligodendrocytes. Thus, the present study may facilitate the therapeutic research of AD.
白质变性和脱髓鞘是阿尔茨海默病（AD）不可忽视的病理表现。由少突胶质细胞组成的髓鞘损伤是AD独特早期病变的基础。参知灵口服液（SZL）是中国食品药品监督管理总局（FDA）批准用于治疗AD的有效中药复方，在临床AD患者中发挥确切治疗作用。然而，其分子机制至今仍不清楚。为此，建立了链脲佐菌素（STZ）诱导的大鼠少突胶质细胞OLN - 93细胞损伤的体外模型，以模拟AD髓鞘的病理变化，并研究SZL保护受损OLN - 93细胞的机制。结果表明，STZ可降低细胞活力，下调OLN - 93细胞中PI3K/Akt - mTOR信号通路的活性以及髓鞘相关蛋白（MBP、MOG和PLP）的表达。SZL含药血清和多奈哌齐（阳性对照）均可保护细胞免受STZ所致损伤。SZL含药血清以剂量和时间依赖性方式提高OLN - 93细胞活力，并增强PI3K/Akt - mTOR信号通路的活性。PI3K抑制剂（LY294002）抑制了SZL含药血清对STZ损伤的OLN - 93细胞的保护作用。此外，mTOR抑制剂雷帕霉素抑制了SZL含药血清引起的细胞活力促进作用以及p - mTOR和MBP的上调。总之，我们的数据表明SZL通过促进少突胶质细胞的PI3K/Akt - mTOR信号通路对AD发挥治疗作用。因此，本研究可能有助于AD的治疗研究。
