Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice

J Ethnopharmacol. 2011 Oct 31;138(1):22-33. doi: 10.1016/j.jep.2011.06.033. Epub 2011 Jul 8.

Abstract

Ethnopharmacological relevance: 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.

Aim of the study: In this study, we aim to investigate the mechanisms of action using an integrative neurofunctional and broad genomics approach.

Materials and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Astragalus Plant
  • Blood Coagulation / drug effects
  • Blood Coagulation / genetics
  • Brain / drug effects*
  • Brain / physiology
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / etiology
  • Brain Ischemia / genetics
  • Cerebral Infarction / prevention & control
  • Drugs, Chinese Herbal / pharmacology*
  • Drugs, Chinese Herbal / therapeutic use
  • Gene Expression / drug effects*
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / genetics
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Phytotherapy
  • Stroke / drug therapy*
  • Stroke / genetics
  • Stroke / mortality
  • Tissue Plasminogen Activator / pharmacology

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Drugs, Chinese Herbal
  • Neuroprotective Agents
  • buyang huanwu
  • Tissue Plasminogen Activator