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Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen–Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K/Akt and ERK Pathways

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Abstract

Oxygen and glucose (OGD) deprivation is one of the most important pathogenic mechanisms in cerebral infarction and is widely used as an in vitro model for ischemic stroke. OGD also damages neural stem cells (NSCs), which are important in brain recovery after cerebral infarction. To enhance recovery, there have been many studies aimed at determining methods to protect NSCs after stroke. Because atorvastatin has diverse protective effects on neural cells, we studied whether it could rejuvenate NSCs injured by OGD. Primary cultured NSCs were exposed to OGD for 8 h, and the main characteristics of stem cells, such as survival, proliferation, migration, and differentiation, were evaluated to confirm the effect of OGD on NSCs. Next, cells were treated with various concentrations of atorvastatin with exposure to OGD for 8 h to confirm whether it could rejuvenate NSCs. OGD significantly affected the survival, proliferation, migration, and differentiation of NSCs. However, treatment with atorvastatin meaningfully restored survival, proliferation, migration, and differentiation of NSCs. These beneficial effects of atorvastatin were blocked by treatment with either a PI3K inhibitor or an ERK inhibitor. In conclusion, OGD damages NSCs and causes them to lose the main characteristics of stem cells so that they cannot contribute to brain recovery after cerebral infarction. However, treatment with atorvastatin after cerebral infarction can effectively rejuvenate NSCs through activating the PI3K and ERK pathways to aid in brain regeneration.

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Funding

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea, which is funded by the Ministry of Science, ICT, and Future Planning (2018R1A2A2A15023219); by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C2160 and HI18C1254); by the Medical Research Center (2017R1A5A2015395); and by the Science Research Program through the National Research Foundation of Korea, which is funded by the Ministry of Science, ICT, and Future Planning (2017R1C1B5076630).

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Author notes

  1. Na-Young Choi and Ji Young Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Hanyang University College of Medicine, Gyeongchun-ro, Guri-Si, 11923, Gyeonggi-do, Republic of Korea

    Na-Young Choi, Mina Hwang, Eun-Hye Lee, Hojin Choi, Kyu-Yong Lee, Young Joo Lee & Seong-Ho Koh

  2. Department of Nuclear Medicine, Hanyang University College of Medicine, Gyeongchun-ro, Guri-Si, 11923, Gyeonggi-do, Republic of Korea

    Ji Young Kim

  3. Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Gyeongchun-ro, Guri-Si, 11923, Gyeonggi-do, Republic of Korea

    Eun-Hye Lee & Seong-Ho Koh

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  1. Na-Young Choi
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Correspondence to Seong-Ho Koh.

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All animal procedures were conducted in accordance with Hanyang University’s guidelines for the care and use of laboratory animals and were approved by the Institutional Animal Care and Use Committee (IACUC) of Hanyang University.

Electronic Supplementary Material

Supplementary Fig. 1

Difference of nestin expression depending on days after differentiation of neural stem cells. Nestin was still expressed in the cells for 9 days after induction of differentiation, but it decreased with time. To confirm whether nestin would disappear with differentiation of NSCs, additional experiments for 11-day differentiation were performed. In these additional experiments, it was confirmed that nestin expression almost disappeared 11 days after differentiation as DCX and GFAP expression increased, indicating complete differentiation of NSCs. (PNG 4052 kb)

High resolution image (TIF 114178 kb)

Supplementary Fig. 2

Effect of atorvastatin on the viability of neuronal stem cells (NSCs) after treatment with 16-h OGD and/or atorvastatin. Exposure to 16-h OGD reduced the viability of NSCs by about 60%, which was considered too low to be used for further experiments that require large amounts of cells, such as Western blotting. Atorvastatin significantly restored viability at concentrations of 0.1 and 1 μM. Data are presented as the mean (% of control) ± SD. Treatment groups were compared with the control group using two-way ANOVA followed by Tukey’s test (a: n=4, b: n=4). *P < 0.05, **P < 0.01 (vs. the control group); # P < 0.05, ## P < 0.01 (vs. the group that was treated with 16-h OGD alone) (PNG 107 kb)

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Choi, NY., Kim, J.Y., Hwang, M. et al. Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen–Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K/Akt and ERK Pathways. Mol Neurobiol 56, 2964–2977 (2019). https://doi.org/10.1007/s12035-018-1267-6

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