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Tetramethylpyrazine Promotes Migration of Neural Precursor Cells via Activating the Phosphatidylinositol 3-Kinase Pathway

Molecular Neurobiology volume 53, pages 6526–6539 (2016)Cite this article

Abstract

Stem cell therapy may provide a novel therapeutic method for the replacement and regeneration of damaged neural cells in the central nervous system. However, insufficient stem cell migrating into the injured regions limits its applications. Although tetramethylpyrazine (TMP) originally isolated from Ligusticum walliichi (Chuanxiong) has been widely used to treat ischemic stroke in the clinic for many years because of its role in neuroprotection, how TMP impacts the migration of neural progenitor/precursor cells (NPCs) and what is the underlying cellular and molecular mechanism remain largely unknown. Here, we found that TMP promoted NPC migration through increasing the expression and secretion of stromal cell-derived factor 1 (SDF-1), a chemokine that has been well demonstrated to direct NPC cell trafficking, in a dose-dependent fashion as analyzed by using different methods. The role of TMP in NPC migration could be inhibited by AMD 3100, a chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist. Further investigation of the molecular mechanisms revealed that TMP treatment rapidly activated phosphatidylinositol 3-kinase (PI3K)/Akt, protein kinase C (PKC), and extracellular signal-regulated kinase (ERK), but not Pyk2, in NPCs. NPC migration could be blocked by using pharmacological inhibitors for these signaling pathways such as LY294002 (a PI3K inhibitor), Myr-ψPKC (a PKC inhibitor), and an ERK1/2 inhibitor. Furthermore, TMP enhanced NPC migration toward the ischemic region in the MCAO rat model. Our findings provide mechanistic insights into the role of TMP in treating the neuropathological diseases, which suggest that TMP may be used as a potent drug for improving NPC migration in stem cell-based therapy.

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Acknowledgments

The investigation was supported by Natural Science Foundation of China (30873394), the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ070825, ZXKT15014), National Major Scientific and Technological Special Project for ‘‘Significant New Drugs Creation’’ (No. 2013ZX09301307).

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    1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China

      Xiangying Kong, Micun Zhong, Xiaohui Su, Qingxia Qin, Hongchang Su, Hongye Wan, Cuiling Liu, Jiajia Wu, Yanjun Zhang & Na Lin

    2. Key Laboratory of Chinese Internal Medicine of MOE and Beijing, Dongzhimen Hospital, Beijing University Chinese Medicine, Beijing, China

      Hongcai Shang & Na Lin

    3. Tianjin State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Traditional Chinese Medicine Pharmacology, Chinese Materia Medica College, Tianjin University of Traditional Chinese Medicine, Tianjin, China

      Yanjun Zhang

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    Suppl. Fig. 1
    figure 9

    Involvement of the SDF-1 and PI3K pathway in NPCs migration induced by TMP in vitro. (a) NPCs were pretreated with AMD 3100 (5 μg/mL) for 2 h, then incubated with LY294002 (10 μM), 3-(2-Aminoethyl)-5-(4-ethoxyphenyl)methylene -2,4- thiazolidinedione hydrochloride (ERK inhibitor, 10 μM), Myr-ψPKC (10 μM) and PF-431396 (2.5 μM) for 30 min at 37 °C, followed by exposing to TMP (50 μg/mL) for another 24 h. Cell migration was monitored under a microscope. The images are representative of three independent experiments. (b) The data are expressed as the mean ± SD of three independent experiments. **P < 0.01,***P < 0.001 versus Control group. # P < 0.05 versus AMD+TMP group (GIF 143 kb)

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    Suppl. Fig. 2
    figure 10

    Involvement of the SDF-1 and PI3K pathway in NPCs migration induced by TMP in vivo. (a) Schematic representation of the time course of experimental design. Adults SD rats were subjected to cerebral ischemia operation, then treated with or without TMP (40 mg/kg) in the presence of AMD 3100 (1 mg/kg) or LY294002 (10 mg/kg) for 3 day. Neurological deficit score (b) and infarction volume by TTC staining (c) in MCAO rats were shown. Cells migration was assessed by showing BrdU (green) and DCX (red) double-labeled cells. (d) The microphotographs showed BrdU+/DCX+ cells at day 21 from the corpus striatum (CS) and the subgranular zone (SGZ). Quantitation of BrdU+/DCX+ cells in the CS (e), SGZ (f) and SVZ (g) at day 7 and 21 after MCAO. Data are represented as the mean ± SD (n = 4-8). *P < 0.05, **P < 0.01, versus sham group. # P < 0.05, ## P < 0.01, versus model group. &P < 0.05, &&P < 0.01, versus TMP only group (GIF 102 kb)

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    Kong, X., Zhong, M., Su, X. et al. Tetramethylpyrazine Promotes Migration of Neural Precursor Cells via Activating the Phosphatidylinositol 3-Kinase Pathway. Mol Neurobiol 53, 6526–6539 (2016). https://doi.org/10.1007/s12035-015-9551-1

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    Keywords

    • Neural precursor cells
    • Migration
    • Stromal cell-derived factor 1
    • Neurogenesis
    • Phosphatidylinositol 3-kinase