Exercise pre-conditioning reduces brain inflammation in stroke via tumor necrosis factor-alpha, extracellular signal-regulated kinase 1/2 and matrix metalloproteinase-9 activity.
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.
Curry
Alecia
A
Department of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Guo
Miao
M
Patel
Rohit
R
Liebelt
Brandon
B
Sprague
Shane
S
Lai
Qin
Q
Zwagerman
Nathan
N
Cao
Frank X
FX
Jimenez
David
D
Ding
Yuchuan
Y
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
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