Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice.
Stroke
; 47(9): 2419-22, 2016 09.
Article
in En
| MEDLINE
| ID: mdl-27470988
ABSTRACT
BACKGROUND AND PURPOSE:
Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke.METHODS:
TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated.RESULTS:
Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant.CONCLUSIONS:
Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Brain Ischemia
/
Plasminogen Activator Inhibitor 1
/
Stroke
/
Carboxypeptidase B2
/
Antibodies, Monoclonal
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Stroke
Year:
2016
Document type:
Article