title: Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection.
abstract: BACKGROUND
  Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI.
  
  
  METHODS
  Spinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α.
  
  
  RESULTS
  LXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4.
  
  
  CONCLUSIONS
  Collectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.
authors.affiliation: Department of Pharmacology, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil. ac.martini@uci.edu.|Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA. ac.martini@uci.edu.|Present address: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697-4545, USA. ac.martini@uci.edu.
authors.forename: Alessandra Cadete
authors.initials: AC
authors.lastname: Martini
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.|Present address: Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Department of Pharmacology, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil.|Present address: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697-4545, USA.
authors.forename: Stefânia
authors.initials: S
authors.lastname: Forner
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Centro de Inovação e Ensaios Pré-Clínicos-CIEnP, Florianópolis, Santa Catarina, 88056-000, Brazil.
authors.forename: Allisson Freire
authors.initials: AF
authors.lastname: Bento
authors.affiliation: Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.affiliation: Department of Pharmacology, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-970, Brazil.
authors.forename: Giles Alexander
authors.initials: GA
authors.lastname: Rae
mesh_terms: D000818:Animals; D019771:Axotomy; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000503:physiopathology*; D007278:Injections, Spinal; D044045:Lipoxins / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000150:complications*
chemical_list: D044045:Lipoxins; C040527:lipoxin A4
keywords: Chronic pain; Lipoxin; Microglia; Neuroinflammation; Spinal cord injury