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

作者：Wang Hsei Wei; Liou Kuo Tong; Wang Yea Hwey; Lu Chung Kuang^*; Lin Yun Lian; Lee I Jung; Huang Sheng Teng; Tsai Yuan Hau; Cheng Yi Chieh; Lin Hung Jui; Shen Yuh Chiang

来源：Journal of Ethnopharmacology, 2011, 138(1): 22-33.

DOI：10.1016/j.jep.2011.06.033

• Apoptosis
• Bu-yang Huan-wu decoction
• Cerebral ischemia-reperfusion (CI/R)
• Functional modules and genetic networks
• Genome-wide transcriptome analysis
• Infarction
• Inflammation
• Mice
• Microarray
• Neurogenesis
• Oxidative stress
• Positron emission tomography (PET)
• Neurological deficits

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 1.0 g/kg) twice daily starting from 2h after ischemia and compared this with vehicle control treatments, recombinant tissue-type plasminogen activator (rt-PA, 10 mg/kg, iv.), and MK-801 (0.2 mg/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 (1.0 g/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 CUR 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.

• 出版日期2011-10-31
• 单位长春大学