title: Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice.
abstract: BACKGROUND
  Bu-yang Huan-wu decoction (BHD) is a famous traditional Chinese medicine formula that has been used clinically in Asia to treat stroke-induced disability for centuries, but the underlying neuroprotective mechanisms are not fully understood.
  
  
  OBJECTIVE
  In this study, we aim to investigate the mechanisms of action using an integrative neurofunctional and broad genomics approach.
  
  
  METHODS
  Male ICR mice were subjected to an acute ischemic stroke by inducing a middle cerebral ischemic/reperfusion (CI/R) injury. To examine whether BHD could extend the lifespan of mice with a stroke, we used oral administration of BHD (0.5 and 1.0g/kg) twice daily starting from 2h after ischemia and compared this with vehicle control treatments, recombinant tissue-type plasminogen activator (rt-PA, 10mg/kg, i.v.), and MK-801 (0.2mg/kg, i.p.). An integrative neurofunctional and genomic approach was performed to elucidate the underlying molecular mechanisms of BHD.
  
  
  RESULTS
  More than 80% of the mice died within 2 days after stroke induction in the vehicle control treatment group. However, the survival rates and life-spans of mice treated with BHD, rt-PA and MK-801 were significantly enhanced as compared to the vehicle-treated CI/R group in all three cases. Mice treated with BHD (1.0g/kg) showed the greatest protective effect across all groups. BHD successfully restored brain function, ameliorated the cerebral infarction, and significantly improved the neurological deficits of the mice with a stroke. BHD also reduced inflammation, oxidative stress, and apoptosis, as well as improved neurogenesis. The molecular impacts of BHD were assessed by genome-wide transcriptome analysis using brains from the CI/R mice. The results showed a total of 377 ischemia-induced probe-sets that were significantly influenced by BHD including 93 probe-sets that were commonly more abundant in BHD-treated and sham mice, and another 284 ischemia-induced probe sets that were suppressed by BHD. Mining the functional modules and genetic networks of these 377 genes revealed a significant upregulation of neuroprotective genes associated with neurogenesis (6 genes) and nervous system development (9 genes), and a significant down-regulation of destructive genes associated with the induction of inflammation (14 genes), apoptosis (15 genes), angiogenesis (11 genes) and blood coagulation (7 genes) by BHD.
  
  
  CONCLUSIONS
  Our results suggested that BHD is able to protect mice against stroke and extend lifespan primarily through a significant down-regulation of genes involved in inflammation, apoptosis, angiogenesis and blood coagulation, as well as an up-regulation of genes mediating neurogenesis and nervous system development. The changes in expression after treatment with BHD are beneficial after ischemic stroke.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Kuo-Tong
authors.initials: KT
authors.lastname: Liou
authors.forename: Yea-Hwey
authors.initials: YH
authors.lastname: Wang
authors.forename: Chung-Kuang
authors.initials: CK
authors.lastname: Lu
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.forename: I-Jung
authors.initials: IJ
authors.lastname: Lee
authors.forename: Sheng-Teng
authors.initials: ST
authors.lastname: Huang
authors.forename: Yuan-Hau
authors.initials: YH
authors.lastname: Tsai
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Cheng
authors.forename: Hung-Jui
authors.initials: HJ
authors.lastname: Lin
authors.forename: Yuh-Chiang
authors.initials: YC
authors.lastname: Shen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D027883:Astragalus Plant; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D002544:Cerebral Infarction / Q000517:prevention & control; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D008517:Phytotherapy; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D018696:Neuroprotective Agents; C460102:buyang huanwu; D010959:Tissue Plasminogen Activator