title: Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABA(B1) receptor expression in transient focal cerebral ischemia in rats.
abstract: OBJECTIVE
  Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) provides neuroprotection against apoptosis in a transient middle cerebral artery occlusion (MCAo) model. This study was to further investigate the anti-apoptotic effect of FA during reperfusion after cerebral ischemia.
  
  
  METHODS
  Rats were subjected to 90 min of cerebral ischemia followed by 3 or 24 h of reperfusion after which they were sacrificed.
  
  
  RESULTS
  Intravenous FA (100 mg/kg) administered immediately after middle cerebral artery occlusion (MCAo) or 2 h after reperfusion effectively abrogated the elevation of postsynaptic density-95 (PSD-95), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine, and cleaved caspase-3 levels as well as apoptosis in the ischemic cortex at 24 h of reperfusion. FA further inhibited Bax translocation, cytochrome c release, and p38 mitogen-activated protein (MAP) kinase phosphorylation. Moreover, FA enhanced the expression of gamma-aminobutyric acid type B receptor subunit 1 (GABA(B1)) in the ischemic cortex at 3 and 24 h of reperfusion. In addition, nitrotyrosine-positive cells colocalized with cleaved caspase-3-positive cells, and phospho-p38 MAP kinase-positive cells colocalized with nitrotyrosine- and Bax-positive cells, indicating a positive relationship among the expression of nitrotyrosine, phospho-p38 MAP kinase, Bax, and cleaved caspase-3. The mutually exclusive expression of GABA(B1) and nitrotyrosine revealed that there is a negative correlation between GABA(B1) and nitrotyrosine expression profiles. Additionally, pretreatment with saclofen, a GABA(B) receptor antagonist, abolished the neuroprotection of FA against nitric oxide (NO)-induced apoptosis.
  
  
  CONCLUSIONS
  FA significantly enhances GABA(B1) receptor expression at early reperfusion and thereby provides neuroprotection against p38 MAP kinase-mediated NO-induced apoptosis at 24 h of reperfusion.
authors.affiliation: Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan, China.
authors.forename: Chin-yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Shan-yu
authors.initials: SY
authors.lastname: Su
authors.forename: Nou-ying
authors.initials: NY
authors.lastname: Tang
authors.forename: Tin-yun
authors.initials: TY
authors.lastname: Ho
authors.forename: Wan-yu
authors.initials: WY
authors.lastname: Lo
authors.forename: Ching-liang
authors.initials: CL
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D003373:Coumaric Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000235:genetics; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003373:Coumaric Acids; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D018080:Receptors, GABA-B; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C004999:ferulic acid; D048051:p38 Mitogen-Activated Protein Kinases