title: Sodium ferulate and n-butylidenephthalate combined with bone marrow stromal cells (BMSCs) improve the therapeutic effects of angiogenesis and neurogenesis after rat focal cerebral ischemia.
abstract: Studies have indicated that bone marrow stromal cell (BMSC) administration is a promising approach for stroke treatment. For our study, we chose sodium ferulate (SF) and n-butylidenephthalide (BP) combined with BMSC, and observed if the combination treatment possessed more significant effects on angiogenesis and neurogenesis post-stroke.
  
  
  
  We established rat permanent middle cerebral artery occlusion (MCAo) model and evaluated ischemic volumes of MCAo, BMSC, SF + BP, Simvastatin + BMSC and SF + BP + BMSC groups with TTC staining on the 7th day after ischemia. Immunofluorescence staining of vascular endothelial growth factor (VEGF) and brain derived neurotrophic factor (BDNF), as well as immunohistochemistry staining of von Willebrand factor (vWF) and neuronal class III β-tubulin (Tuj1) were performed in ischemic boundary zone (IBZ), furthermore, to understand the mechanism, western blot was used to investigate AKT/mammalian target of rapamycin (mTOR) signal pathway in ischemic cortex. We also tested BMSC derived-VEGF and BDNF expressions by western blot assay in vitro.
  
  
  
  SF + BP + BMSC group obviously decreased infarction zone, and elevated the expression of VEGF and the density and perimeter of vWF-vessels as same as Simvastatin + BMSC administration; moreover, its effects on BDNF and Tuj1 expressions were superior to Simvastatin + BMSC treatment in IBZ. Meanwhile, it showed that SF and BP combined with BMSC treatment notably up-regulated AKT/mTOR signal pathway compared with SF + BP group and BMSC alone post-stroke. Western blot results showed that SF and BP treatment could promote BMSCs to synthesize VEGF and BDNF in vitro.
  
  
  
  We firstly demonstrate that SF and BP combined with BMSC can significantly improve angiogenesis and neurogenesis in IBZ following stroke. The therapeutic effects are associated with the enhancement of VEGF and BDNF expressions via activation of AKT/mTOR signal pathway. Furthermore, triggering BMSC paracrine function of SF and BP might contribute to amplifying the synergic effects of the combination treatment.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China. yhzhao@must.edu.mo.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China.
authors.forename: Naiwei
authors.initials: N
authors.lastname: Liu
authors.affiliation: Biomedical Imaging Research Center, National Yang Ming University, Taipei, Taiwan.
authors.forename: Chienchih
authors.initials: C
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao, People's Republic of China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: Weikang
authors.initials: W
authors.lastname: Wu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000628:therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003373:Coumaric Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D010641:Phenotype; D010796:Phthalic Anhydrides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000628:therapy; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003373:Coumaric Acids; D010796:Phthalic Anhydrides; D042461:Vascular Endothelial Growth Factor A; C004999:ferulic acid; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C026105:butylidenephthalide
keywords: Angiogenesis; Bone marrow stromal cells; Ischemic stroke; Neurogenesis; Sodium ferulate; n-Butylidenephthalide