title: Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-alpha, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity.
abstract: OBJECTIVE
  We sought to determine whether cerebral inflammation in ischemic rats was reduced by a neuroprotective action of pre-ischemic tumor necrosis factor-alpha up-regulation, which down-regulated matrix metalloproteinase-9 activity via extracellular signal-regulated kinase 1/2 phosphorylation.
  
  
  METHODS
  Adult male Sprague-Dawley rats were subjected to 30 minutes of exercise on a treadmill for 3 weeks. Stroke was induced by a 2 hour middle cerebral artery occlusion using an intraluminal filament. The exercised animals were treated with tumor necrosis factor-alpha antibody, UO126 (extracellular signal-regulated kinase 1/2 inhibitor), or both UO126 and doxycycline (matrix metalloproteinase-9 inhibitor). Brain infarct volume was assessed using Nissl staining. Leukocyte infiltration was evaluated using myeloperoxidase immunostaining. Intercellular adhesion molecule-1 and matrix metalloproteinase protein levels were determined by Western blot, and enzyme activity was evaluated using zymography.
  
  
  RESULTS
  There was a significant decrease in neurological deficits, brain infarct volume and leukocyte infiltration, in association with reduction in matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression in exercised animals. Exercised animals treated with either tumor necrosis factor-alpha antibody or with UO126 showed a reversal of neurological outcome, infarct volume and leukocyte infiltration. Matrix metalloproteinase-9 activity was reversed, at least partially, but the intercellular adhesion molecule-1 expression was not. Neuroprotection remained when the exercised ischemic rats were treated with both UO126 and doxycycline.
  
  
  CONCLUSIONS
  These results suggest that exercise-induced up-regulation of tumor necrosis factor-alpha before stroke and extracellular signal-regulated kinase 1/2 phosphorylation play a role in decreasing brain inflammation by regulating matrix metalloproteinase-9 activity.
authors.affiliation: Department of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Alecia
authors.initials: A
authors.lastname: Curry
authors.forename: Miao
authors.initials: M
authors.lastname: Guo
authors.forename: Rohit
authors.initials: R
authors.lastname: Patel
authors.forename: Brandon
authors.initials: B
authors.lastname: Liebelt
authors.forename: Shane
authors.initials: S
authors.lastname: Sprague
authors.forename: Qin
authors.initials: Q
authors.lastname: Lai
authors.forename: Nathan
authors.initials: N
authors.lastname: Zwagerman
authors.forename: Frank X
authors.initials: FX
authors.lastname: Cao
authors.forename: David
authors.initials: D
authors.lastname: Jimenez
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9