title: Xiao-Xu-Ming decoction preserves mitochondrial integrity and reduces apoptosis after focal cerebral ischemia and reperfusion via the mitochondrial p53 pathway.
abstract: BACKGROUND
  Xiao-Xu-Ming decoction (XXMD) has been used to treat stroke and other neurological diseases for more than 1000 years. The purpose of this study was to investigate the effects of XXMD on mitochondrial damage and apoptosis after cerebral ischemia and reperfusion.
  
  
  METHODS
  Male Sprague-Dawley rats were randomly divided into 3 groups: sham, cerebral ischemia and reperfusion (I/R), and cerebral ischemia and reperfusion plus XXMD (60 g/kg/day) (XXMD60). Focal cerebral ischemia and reperfusion models were induced by middle cerebral artery occlusion. Cerebral ischemic injury was evaluated by hematoxylin and eosin staining. Ultrastructural features of mitochondria in the penumbra of the ischemic cortex were analyzed by transmission electron microscopy. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) staining and cleaved caspase 3 immunohistochemistry. Proteins in the mitochondrial p53 pathway were detected by western blot and immunofluorescence.
  
  
  RESULTS
  The results showed that XXMD treatment markedly attenuated ischemic changes, preserved mitochondrial integrity, and significantly reduced apoptosis. In addition, we found that XXMD treatment reduced p53 and Bax levels and increased Bcl-2 levels in mitochondrial fractions. XXMD significantly blocked the release of cytochrome c and Smac/Diablo from mitochondria, and inhibited activation of caspase 9 and caspase 3 in cytoplasmic fractions. Increased expression of c-IAP1 was observed in the XXMD60 group.
  
  
  CONCLUSIONS
  The findings demonstrated that XXMD protected mitochondria from ischemic injury and inhibited apoptosis. The mitochondrial p53 pathway could be partially involved in the protective effects.
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Lan
authors.affiliation: Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China; Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Wang
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Li
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Xu
authors.affiliation: Department of Integrative Medicine, Zhongshan Hospital, Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China. Electronic address: dingfangcai@163.com.
authors.forename: Ding-Fang
authors.initials: DF
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000473:pathology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004365:Drugs, Chinese Herbal; D016159:Tumor Suppressor Protein p53; C548754:xiao-xu-ming
keywords: Apoptosis; Focal cerebral ischemia and reperfusion; Mitochondria integrity; Mitochondrial p53 pathway; Xiao-Xu-Ming decoction