title: Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats.
abstract: OBJECTIVE
  Lipoxin A4 (LXA4) has been reported to reduce inflammation in several neurological injury models. We studied the effects of LXA4 on neuroinflammation after subarachnoid hemorrhage (SAH) in a rat model.
  
  
  METHODS
  Two hundred and thirty-eight Sprague-Dawley male rats, weight 280-320 g, were used. Exogenous LXA4 (0.3 and 1.0 nmol) were injected intracerebroventricularly at 1.5 hours after SAH. Neurological scores, brain water content, and blood-brain barrier were evaluated at 24 hours after SAH; Morris water maze and T-maze tests were examined at 21 days after SAH. The expression of endogenous LXA4 and its receptor formyl peptide receptor 2 (FPR2), as well as p38, interleukin-1β, and interleukin-6 were studied either by ELISA or by Western blots. Neutrophil infiltration was observed by myeloperoxidase staining. FPR2 siRNA was used to knock down LXA4 receptor.
  
  
  RESULTS
  The expression of endogenous LXA4 decreased, and the expression of FPR2 increased after SAH. Exogenous LXA4 decreased brain water content, reduced Evans blue extravasation, and improved neurological functions and improved the learning and memory ability after SAH. LXA4 reduced neutrophil infiltration and phosphorylation of p38, interleukin-1β, and interleukin-6. These effects of LXA4 were abolished by FPR2 siRNA.
  
  
  CONCLUSIONS
  Exogenous LXA4 inhibited inflammation by activating FPR2 and inhibiting p38 after SAH. LXA4 may serve as an alternative treatment to relieve early brain injury after SAH.
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Zongduo
authors.initials: Z
authors.lastname: Guo
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Zhen-Ni
authors.initials: ZN
authors.lastname: Guo
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Yibo
authors.initials: Y
authors.lastname: Ou
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Yue
authors.initials: Y
authors.lastname: He
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Cheng
authors.initials: C
authors.lastname: Yin
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.).
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, CA (Z.G., Q.H., L.X., Z.-N.G., Y.O., Y.H., C.Y., J.T., J.H.Z.); and Department of Neurosurgery, the 1st Affiliated Hospital of Chongqing Medical University, Chongqing, China (Z.G., X.S.). johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001929:Brain Edema / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D007249:Inflammation; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D044045:Lipoxins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D009483:Neuropsychological Tests; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D065853:Spatial Learning / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D044045:Lipoxins; D044067:Receptors, Lipoxin; C482540:lipoxin A(4) receptor, rat; C040527:lipoxin A4; D048051:p38 Mitogen-Activated Protein Kinases
keywords: blood–brain barrier; formyl peptide receptor 2; inflammation; lipoxin A4; subarachnoid hemorrhage