title: Tetramethylpyrazine Promotes Migration of Neural Precursor Cells via Activating the Phosphatidylinositol 3-Kinase Pathway.
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.
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. xykong@icmm.ac.cn.
authors.forename: Xiangying
authors.initials: X
authors.lastname: Kong
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Micun
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Su
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Qingxia
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Hongchang
authors.initials: H
authors.lastname: Su
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Wan
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Chinese Internal Medicine of MOE and Beijing, Dongzhimen Hospital, Beijing University Chinese Medicine, Beijing, China.
authors.forename: Hongcai
authors.initials: H
authors.lastname: Shang
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China.|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.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. nlin@icmm.ac.cn.|Key Laboratory of Chinese Internal Medicine of MOE and Beijing, Dongzhimen Hospital, Beijing University Chinese Medicine, Beijing, China. nlin@icmm.ac.cn.
authors.forename: Na
authors.initials: N
authors.lastname: Lin
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12; D011719:Pyrazines; D058539:Phosphatidylinositol 3-Kinase; D020928:Mitogen-Activated Protein Kinases; C017953:tetramethylpyrazine
keywords: Migration; Neural precursor cells; Neurogenesis; Phosphatidylinositol 3-kinase; Stromal cell-derived factor 1