Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke

M. Guo, B. Cox, S. Mahale, W. Davis, A. Carranza, K. Hayes, S. Sprague, D. Jimenez, Y. Ding

Research output: Contribution to journalArticle

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Abstract

Exercise reduces ischemia and reperfusion (I/R) injury in the rat stroke model. We investigated whether pre-ischemic exercise ameliorates blood-brain barrier (BBB) dysfunction in stroke by reducing matrix metalloproteinase (MMP)-9 expression and strengthening basal lamina. Adult male Sprague-Dawley rats were subjected to a 30 min exercise program on a treadmill 5 days a week for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament in the exercised and non-exercised groups. Brain infarction was measured and neurological deficits were scored. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Expression of collagen IV, the major component of basal lamina essential for maintenance of the endothelial permeability barrier, was quantitatively detected by Western blot and immunocytochemistry. Ex vivo techniques were used to compare collagen IV-labeled vessels in response to ischemic insult. Temporal relationship of expression of MMP-9 and its endogenous inhibitor, the tissue inhibitors of metalloproteinase-1 (TIMP-1), was determined by real-time PCR for mRNA and Western blot for protein during reperfusion. Brain edema and Evans Blue leakage were both significantly (P<0.01) reduced after stroke in the exercised group, in association with reduced brain infarct volume and neurological deficits. Western blot analysis indicated that exercise enhanced collagen IV expression and reduced the collagen loss after stroke. Immunocytochemistry demonstrated that collagen IV-labeled vessels were significantly (P<0.01) increased in exercised rats. In the ex vivo study, after exercised brains were incubated with ischemic brain tissue, a significantly (P<0.01) higher level of collagen IV-labeled vessels was observed as compared with non-exercised brains following the same treatment. The ex vivo study also revealed a key role of MMP-9 in exercise-strengthened collagen IV expression against I/R injury. TIMP-1 protein levels were significantly (P<0.01) increased by exercise. Our results indicate that pre-ischemic exercise reduces brain injury by improving BBB function and enhancing basal lamina integrity in stroke. This study suggests that the neuroprotective effect of physical exercise is associated with an imbalance of MMP-9 and TIMP-1 expression.

Original languageEnglish (US)
Pages (from-to)340-351
Number of pages12
JournalNeuroscience
Volume151
Issue number2
DOIs
StatePublished - Jan 24 2008

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Matrix Metalloproteinase 9
Blood-Brain Barrier
Collagen
Stroke
Tissue Inhibitor of Metalloproteinase-1
Basement Membrane
Evans Blue
Western Blotting
Brain Edema
Brain
Reperfusion Injury
Immunohistochemistry
Brain Infarction
Matrix Metalloproteinase Inhibitors
Middle Cerebral Artery Infarction
Neuroprotective Agents
Brain Injuries
Reperfusion
Sprague Dawley Rats
Real-Time Polymerase Chain Reaction

Keywords

  • basal lamina
  • collagen IV
  • ECM
  • ex vivo
  • ischemia and reperfusion injury
  • TIMP-1

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. / Guo, M.; Cox, B.; Mahale, S.; Davis, W.; Carranza, A.; Hayes, K.; Sprague, S.; Jimenez, D.; Ding, Y.

In: Neuroscience, Vol. 151, No. 2, 24.01.2008, p. 340-351.

Research output: Contribution to journalArticle

Guo, M, Cox, B, Mahale, S, Davis, W, Carranza, A, Hayes, K, Sprague, S, Jimenez, D & Ding, Y 2008, 'Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke', Neuroscience, vol. 151, no. 2, pp. 340-351. https://doi.org/10.1016/j.neuroscience.2007.10.006
Guo, M. ; Cox, B. ; Mahale, S. ; Davis, W. ; Carranza, A. ; Hayes, K. ; Sprague, S. ; Jimenez, D. ; Ding, Y. / Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. In: Neuroscience. 2008 ; Vol. 151, No. 2. pp. 340-351.
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