title: The role of PPAR activation during the systemic response to brain injury.
abstract: Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain. Here, we sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury.
  
  
  
  A 1-h intraluminal thread middle cerebral artery occlusion (MCAO) model followed by a 6-h reperfusion was performed in C57/BL6 mice. Quantitative reverse transcriptase-polymerase chain reaction was then used to measure hepatic expression of chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine ligand 10 (CXCL10) and serum amyloid A-1 (SAA-1), and immunohistochemical analysis was used to quantify brain and hepatic neutrophil infiltration following stroke.
  
  
  
  The MCAO and sham surgery induced the expression of all three acute phase reactants. A 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the APR.
  
  
  
  The data highlight a novel mechanism of action for fenofibrate and lend further evidence towards the promotion of its use as a prophylactic therapy in patients at risk of cerebral ischaemia. Further research is required to elucidate the mechanistic explanation underlying its actions.
authors.affiliation: Department of Pharmacology, Experimental Neuropathology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.|EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, Lille, Cedex, 59045, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Losey
authors.affiliation: North Bristol NHS Trust, Southmead Road, Bristol, BS10 5NB, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Ladds
authors.affiliation: EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, Lille, Cedex, 59045, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Laprais
authors.affiliation: Department of Pharmacology, Experimental Neuropathology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Borna
authors.initials: B
authors.lastname: Guevel
authors.affiliation: Department of Pharmacology, Experimental Neuropathology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Burns
authors.affiliation: EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, Lille, Cedex, 59045, France. regis.bordet@univ-lille2.fr.
authors.forename: Regis
authors.initials: R
authors.lastname: Bordet
authors.affiliation: Department of Pharmacology, Experimental Neuropathology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. daniel.anthony@pharm.ox.ac.uk.|EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, Lille, Cedex, 59045, France. daniel.anthony@pharm.ox.ac.uk.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D054360:Chemokine CXCL1 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000008:administration & dosage; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000685:Serum Amyloid A Protein / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; C475895:Cxcl1 protein, mouse; C485433:Cxcl10 protein, mouse; D018696:Neuroprotective Agents; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; C484300:Saa4 protein, mouse; D000685:Serum Amyloid A Protein; D011345:Fenofibrate