OBJECTIVES: 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. DISCUSSION: Overall, our data suggest that Nrf2 upregulation is involved in the neuroprotective effects of LXA4 and may be ALXR independent.
OBJECTIVES: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. DISCUSSION: Overall, our data suggest that Nrf2 upregulation is involved in the neuroprotective effects of LXA4 and may be ALXR independent.
Authors: Magnus Bäck; William S Powell; Sven-Erik Dahlén; Jeffrey M Drazen; Jilly F Evans; Charles N Serhan; Takao Shimizu; Takehiko Yokomizo; G Enrico Rovati Journal: Br J Pharmacol Date: 2014-07-12 Impact factor: 8.739
Authors: Rafael I Jaén; Sergio Sánchez-García; María Fernández-Velasco; Lisardo Boscá; Patricia Prieto Journal: Front Immunol Date: 2021-04-23 Impact factor: 7.561
Authors: Kimberly E Hawkins; Kelly M DeMars; Jon C Alexander; Lauren G de Leon; Sean C Pacheco; Christina Graves; Changjun Yang; Austin O McCrea; Jan C Frankowski; Timothy J Garrett; Marcelo Febo; Eduardo Candelario-Jalil Journal: Brain Behav Date: 2017-04-12 Impact factor: 2.708