title: Ferulic Acid Administered at Various Time Points Protects against Cerebral Infarction by Activating p38 MAPK/p90RSK/CREB/Bcl-2 Anti-Apoptotic Signaling in the Subacute Phase of Cerebral Ischemia-Reperfusion Injury in Rats.
abstract: This study aimed to evaluate the effects of ferulic acid (FA) administered at various time points before or after 30 min of middle cerebral artery occlusion (MCAo) followed by 7 d of reperfusion and to examine the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in the cortical penumbra.
  
  
  
  FA was intravenously administered to rats at a dose of 100 mg/kg 24 h before ischemia (B-FA), 2 h before ischemia (P-FA), immediately after ischemic insult (I-FA), 2 h after reperfusion (R-FA), or 24 h after reperfusion (D-FA).
  
  
  
  Our study results indicated that P-FA, I-FA, and R-FA effectively reduced cerebral infarct areas and neurological deficits. P-FA, I-FA, and R-FA significantly downregulated glial fibrillary acidic protein (GFAP), mitochondrial Bax, cytochrome c, and cleaved caspase-3 expression, and effectively restored the phospho-p38 MAPK (p-p38 MAPK)/p38 MAPK ratio, phospho-90 kDa ribosomal S6 kinase (p-p90RSK) expression, phospho-Bad (p-Bad) expression, the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio, the cytosolic and mitochondrial Bcl-2/Bax ratios, and the cytosolic Bcl-xL/Bax ratio in the cortical penumbra 7 d after reperfusion. SB203580, a specific inhibitor of p38 MAPK, administered 30 min prior to ischemia abrogated the downregulating effects of I-FA on cerebral infarction, and mitochondrial Bax and cleaved caspase-3 expression, and the upregulating effects of I-FA on the p-p38 MAPK/p38 MAPK ratio, p-p90RSK expression, p-Bad expression, and the p-CREB/CREB, and cytosolic and mitochondrial Bcl-2/Bax ratios.
  
  
  
  Our study results thus indicate that P-FA, I-FA, and R-FA effectively suppress reactive astrocytosis and exert neuroprotective effects against cerebral infarction by activating p38 MAPK signaling. The regulating effects of P-FA, I-FA, and R-FA on Bax-induced apoptosis result from activation of the p38 MAPK/p90RSK/CREB/Bcl-2 signaling pathway, and eventually contribute to inhibition of the cytochrome c-mediated caspase-3-dependent apoptotic pathway in the cortical penumbra 7 d after reperfusion.
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.|Department of Chinese Medicine, Hui-Sheng Hospital, 42056, Taichung, Taiwan.
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Nou-Ying
authors.initials: NY
authors.lastname: Tang
authors.affiliation: School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Shung-Te
authors.initials: ST
authors.lastname: Kao
authors.affiliation: Department of Chinese Medicine, China Medical University Hospital, 40447, Taichung, Taiwan.|Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D003373:Coumaric Acids / Q000627:therapeutic use*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003373:Coumaric Acids; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C004999:ferulic acid; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048051:p38 Mitogen-Activated Protein Kinases