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. 2020 Jul 24:2020:4527283.
doi: 10.1155/2020/4527283. eCollection 2020.

Shenzhiling Oral Liquid Protects STZ-Injured Oligodendrocyte through PI3K/Akt-mTOR Pathway

Zhenhong Liu  1   2 , Gaofeng Qin  1   2 , Lulu Mana  1   2   3 , Shuaiyang Huang  1   2 , Yahan Wang  1   2 , Pengwen Wang  1   2
Affiliations

Shenzhiling Oral Liquid Protects STZ-Injured Oligodendrocyte through PI3K/Akt-mTOR Pathway

Zhenhong Liu et al. Evid Based Complement Alternat Med. .

Abstract

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.

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Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Extracted ion chromatographs from standard solution (a), SZL (b), and SZL-medicated serum (c).
Figure 2
Figure 2
An in vitro mode of STZ-induced OLN-93 cell injury was established. (a) The cell viability of OLN-93 cells treated with STZ (0.001 mM–10 mM) for 1–24 h was detected by CCK-8. Each point represents the mean ± SD of n = 6 experiments. (b) Morphological changes of OLN-93 cells under microscope (scale = 100 μm) after treatment with STZ at different concentrations for 3 hours was observed. (c) The relative LDH leakage of OLN-93 cells was determined after treatment with STZ at different concentrations for 3 h. Each point represents the mean ± SD of n = 6 experiments. Changes in IR (d) and IRS1 (e) mRNA transcription levels in OLN-93 cells after STZ treatment for 3 h were observed by qPCR. Mann–Whitney test was used to compare the difference of IR and IRS1 mRNA relative transcript level between control and STZ group. Each point represents the median (IQR) of n = 4 experiments. ∗P < 0.05 and ∗∗P < 0.01, significantly different from control group. IQR means interquartile range.
Figure 3
Figure 3
Effect of SZL-medicated serum (a–c) and donepezil (d) on cell viability of STZ-induced injury of OLN-93 cells. C, control group; M, model group; SZL, SZL-medicated serum group; Don, donepezil group. ∗P < 0.05 and ∗∗P < 0.01, significantly different from control group; ΔP < 0.05 and ΔΔP < 0.01, significantly different from model group. Each point represents the mean ± SD of n = 6 experiments.
Figure 4
Figure 4
Effect of SZL-medicated serum on expression of PI3K (a), Akt (b), p-Akt (c), mTOR (d), and p-mTOR (e) proteins in injured OLN-93 cells. C, control group; M, model group; Don, donepezil group; SZL, SZL-medicated serum group. ∗∗P < 0.01, significantly different from control group; ΔΔP < 0.01, significantly different from model group. Each point represents the mean ± SD of n = 6 experiments.
Figure 5
Figure 5
Effect of SZL-medicated serum on expression of MBP (a), MOG (b), and PLP (c) proteins in injured OLN-93 cells. C, control group; M, model group; Don, donepezil group; SZL, SZL-medicated serum group. ∗∗P < 0.01, significantly different from control group; ΔΔP < 0.01, significantly different from model group. Each point represents the mean ± SD of n = 6 experiments.
Figure 6
Figure 6
Effect of SZL-medicated serum on expression of Akt (a), mTOR (b), and MBP (c) mRNA in injured OLN-93 cells. C, control group; M, model group; Don, donepezil group; SZL, SZL-medicated serum group. ∗∗P < 0.01, significantly different from control group; ΔΔP < 0.01, significantly different from model group. Each point represents the mean ± SD of n = 6 experiments.
Figure 7
Figure 7
The role of LY294002 on protective effect of SZL-medicated serum on STZ-injured OLN-93 cells. (a) Effect of LY294002 on SZL-medicated serum-increased cell viability of injured OLN-93 cells. Effect of LY294002 on SZL-medicated serum-induced up-regulation of p-Akt (b) and MBP (c, d) in injured OLN-93 cells; C, control group; M, model group; M + LY-294, model + LY294002 group; Don, donepezil group; Don + LY-294, donepezil + LY294002 group; SZL, SZL-medicated serum group; SZL + LY-294, SZL-medicated serum + LY294002 group. ∗∗P < 0.01, significantly different from control group. ΔP < 0.05 and ΔΔP < 0.01, significantly different from model group. ★★P < 0.01, significantly different from donepezil group; ▼▼P < 0.01, significantly different from SZL-medicated serum group. Each point represents the mean ± SD of n = 6 experiments.
Figure 8
Figure 8
The role of rapamycin on protective effect of SZL-medicated serum on STZ-injured OLN-93 cells. (a) Effect of rapamycin on SZL-medicated serum-increased cell viability of injured OLN-93 cells. Effect of rapamycin on SZL-medicated serum-induced upregulation of p-mTOR (b) and MBP (c, d) in injured OLN-93 cells. C, control group; M, model group; M + RAPA, model + rapamycin group; Don, donepezil group; Don + RAPA, donepezil + rapamycin group; SZL, SZL-medicated serum group; SZL + RAPA, SZL-medicated serum + rapamycin group. ∗∗P < 0.01, significantly different from control group; ΔP < 0.05 and ΔΔP < 0.01, significantly different from model group; ★P < 0.05 and ★★P < 0.01, significantly different from donepezil group; ▼▼P < 0.01, significantly different from SZL-medicated serum group. Each point represents the mean ± SD of n = 6 experiments.
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