title: Lipoxin A4 ameliorates cerebral ischaemia/reperfusion injury through upregulation of nuclear factor erythroid 2-related factor 2.
abstract: OBJECTIVE
  Lipoxin A4 (LXA4) is a potent anti-inflammatory mediator that exerts a neuroprotective effect following cerebral ischaemia/reperfusion (I/R) injury. However, little is known about the underlying mechanisms. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is generally considered to reduce cerebral I/R injury. Nuclear factor erythroid 2-related factor 2 can induce haeme oxygenase-1 (HO-1) and glutathione (GSH) expression to combat increased oxidative stress. The present study aimed to investigate the effects of Nrf2 signalling on LXA4-mediated neuroprotection.
  
  
  METHODS
  Adult male Sprague Dawley rats were subjected to 2-hour middle cerebral artery occlusion followed by 24-hour reperfusion. Rats were randomly divided into four groups: Sham, I/R, LXA4, and LXA4+butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc2) (all n = 24). Brain infarction was detected by 2,3,5-triphenyltetrazolium chloride staining. After 24 hours of reperfusion, Nrf2, HO-1, and p62 expression levels were determined by western blot, and GSH synthesis was assessed.
  
  
  RESULTS
  Lipoxin A4 effectively reduced infarct volumes and improved neurological scores. These effects were partially blocked by Boc2, a specific antagonist of the LXA4 receptor (ALXR). Lipoxin A4 induced Nrf2 expression and its nuclear translocation, as well as HO-1 expression and GSH synthesis; Boc2 did not block these effects. The excess p62 accumulation induced by LXA4 might be closely related to Nrf2 activation.
  
  
  CONCLUSIONS
  Overall, our data suggest that Nrf2 upregulation is involved in the neuroprotective effects of LXA4 and may be ALXR independent.
authors.affiliation: Wuhan General Hospital of Guangzhou Command PLA, Wuhan, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wu
authors.forename: Zi Jian
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Sen
authors.initials: S
authors.lastname: Miao
authors.forename: Lin Bing
authors.initials: LB
authors.lastname: Zou
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Du Yun
authors.initials: du Y
authors.lastname: Ye
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.forename: Hong Hua
authors.initials: HH
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D044045:Lipoxins / Q000627:therapeutic use*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein; D012720:Severity of Illness Index; D015854:Up-Regulation
chemical_list: D006360:Heat-Shock Proteins; D044045:Lipoxins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D009842:Oligopeptides; D000071456:Sequestosome-1 Protein; C491079:Sqstm1 protein, rat; C040527:lipoxin A4; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D005978:Glutathione