Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats.
OBJECTIVE
Most experimental models of cerebral ischemia use mechanical methods of occlusion and reperfusion. However, differences between mechanical reperfusion versus clot thrombolysis may influence reperfusion injury profiles. In this study we compared blood flow recovery, blood-brain barrier (BBB) permeability, and matrix metalloproteinase-9 (MMP-9) expression in cortex after mechanical versus thrombolytic reperfusion in rat focal ischemia.


METHODS
Male spontaneously hypertensive rats were used. Mechanical ischemia/reperfusion was achieved with the use of an intraluminal filament to occlude the middle cerebral artery for 2 hours. Thrombolytic reperfusion was achieved by administering tissue plasminogen activator at 2 hours after embolic focal ischemia. Regional cortical blood flow was monitored by laser-Doppler flowmetry. BBB permeability in cortex was measured by Evans blue dye leakage. Cortical MMP-9 levels were assessed with zymography and immunohistochemistry.


RESULTS
Blood flow recovery during mechanical reperfusion was complete in both central and peripheral areas of ischemic cortex. However, after thrombolysis, reperfusion was incomplete, with moderate recovery in the periphery only. BBB permeability was mainly increased in the central regions of the ischemic cortex after mechanical reperfusion but was increased in both central and peripheral areas after thrombolysis. Overall, MMP-9 levels were higher after embolic versus mechanical ischemia/reperfusion, even though ischemic injury was similar in both models at 24 hours.


CONCLUSIONS
There are significant differences in the profiles of blood flow recovery, BBB leakage, and MMP-9 upregulation in mechanical versus thrombolytic reperfusion after focal ischemia.
Aoki
Toshiaki
T
Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass 02129, USA.
Sumii
Toshihisa
T
Mori
Tatsuro
T
Wang
Xiaoying
X
Lo
Eng H
EH
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005070:Evans Blue; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D020766:Intracranial Embolism / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051381:Rats; D011918:Rats, Inbred SHR; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects
D005343:Fibrinolytic Agents; D005070:Evans Blue; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9