Erythropoietin attenuates intracerebral hemorrhage by diminishing matrix metalloproteinases and maintaining blood-brain barrier integrity in mice.
The protective mechanism of recombinant human erythropoietin (rhEPO) on blood-brain barrier (BBB) after brain injury is associated with the attenuation of neuro-inflammation. We hypothesize that rhEPO treatment after intracerebral hemorrhage (ICH) modulates matrix metalloproteinase (MMP) activity, maintains BBB integrity, and reduces BBB breakdown-associated inflammation. Adult male 129S2/sv mice were subjected to autologous whole blood-induced ICH. rhEPO or saline was administered intraperitoneally immediately after surgery and for 3 more days until day of sacrifice. BBB permeability was measured by Evans blue leakage, and edema was assessed by brain water content. Immunofluorescence and Western blotting were performed to detect expression of tight junction marker occludin, type IV collagen, MMPs, tissue inhibitor of metalloproteinase (TIMP), and glial fibrillary acidic protein, rhEPO prevented Evans blue leakage, reduced brain edema, and preserved expression of occludin and collagen IV. rhEPO treatment decreased MMP-2 expression, increased TIMP-2 expression, and reduced the number of reactive astrocytes in the brain compared to saline control. We conclude that rhEPO reduces MMP activity, BBB disruption, and the glial cell inflammatory reaction 3 days after ICH. Our study provides additional evidence for the mechanism of rhEPO's neurovascular protective effects and a potential clinical application in the treatment of ICH.
Li
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Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
Ogle
M E
ME
Wallace
G C
GC
Lu
Z Y
ZY
Yu
S P
SP
Wei
L
L
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology*; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000627:therapeutic use*; D005070:Evans Blue; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D011994:Recombinant Proteins; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D024141:Collagen Type IV; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D004921:Erythropoietin; D005070:Evans Blue; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2