Inhibition of Vascular Matrix Metalloproteinase-9 to Treat Ischemic Injury

Abstract

Methods and pharmaceutical compositions for treating ischemic injury are provided. The methods include administering a therapeutically effective amount of a vascular matrix metalloproteinase 9 (MMP-9) inhibitor that reduces ischemic injury in a subject.

1 . A method for reducing injury from ischemia or reperfusion comprising:
 determining a subject will be or is in need of therapy to reduce injury from ischemia or reperfusion; and   administering intravenously to the subject a therapeutically effective amount of a vascular matrix metalloproteinase 9 (MMP-9) inhibitor, wherein the MMP-9 inhibitor is an antibody or fragment thereof that binds MMP-9 and does not cross the intact blood-brain barrier to reduce injury from ischemia or reperfusion.   
     
     
         2 . The method of  claim 1 , wherein the subject is a human. 
     
     
         3 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor does not specifically bind matrix metalloproteinases other than MMP-9. 
     
     
         4 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor is a monoclonal antibody or fragment thereof. 
     
     
         5 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor is administered following ischemic stroke in the subject. 
     
     
         6 . The method of  claim 5 , wherein the vascular MMP-9 inhibitor is administered at least fifteen minutes after ischemic stroke in the subject. 
     
     
         7 . The method of  claim 6 , wherein the vascular MMP-9 inhibitor is administered at least thirty minutes after ischemic stroke in the subject. 
     
     
         8 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor is administered before ischemic stroke in the subject. 
     
     
         9 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor decreases vascular MMP-9 activity in the subject. 
     
     
         10 . The method of  claim 1 , wherein administration of the vascular MMP-9 inhibitor decreases cerebral infarction, ischemic cell death, brain swelling, brain hemorrhage, blood-brain barrier breakdown, fibrin deposition, or a combination thereof. 
     
     
         11 . The method of  claim 1 , wherein the vascular MMP-9 inhibitor specifically binds a catalytic subunit of MMP-9. 
     
     
         12 . The method of  claim 1 , wherein the subject has ischemic injury to a tissue selected from a brain, a liver, a limb, a heart, or a combination thereof. 
     
     
         13 . A method for preventing injury from ischemia or reperfusion comprising:
 determining a subject will be or is in need of therapy to prevent injury from ischemia or reperfusion; and   administering intravenously to the subject a therapeutically effective amount of a vascular matrix metalloproteinase 9 (MMP-9) inhibitor, wherein the MMP-9 inhibitor is an antibody or fragment thereof that binds MMP-9 and does not cross the intact blood-brain barrier to prevent injury from ischemia or reperfusion.   
     
     
         14 . The method of  claim 13 , wherein the subject is a human. 
     
     
         15 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor does not specifically bind matrix metalloproteinases other than MMP-9. 
     
     
         16 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor is a monoclonal antibody or fragment thereof. 
     
     
         17 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor is administered following ischemic stroke in the subject. 
     
     
         18 . The method of  claim 17 , wherein the vascular MMP-9 inhibitor is administered at least fifteen minutes after ischemic stroke in the subject. 
     
     
         19 . The method of  claim 17 , wherein the vascular MMP-9 inhibitor is administered at least thirty minutes after ischemic stroke in the subject. 
     
     
         20 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor is administered before ischemic stroke in the subject. 
     
     
         21 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor decreases vascular MMP-9 activity in the subject. 
     
     
         22 . The method of  claim 13 , wherein the vascular MMP-9 inhibitor specifically binds a catalytic subunit of MMP-9. 
     
     
         23 . The method of  claim 13 , wherein the administration of the vascular MMP-9 inhibitor prevents injury from ischemia or reperfusion of cerebral infarction, ischemic cell death, brain swelling, brain hemorrhage, blood-brain barrier breakdown, fibrin deposition, or a combination thereof. 
     
     
         24 . The method of  claim 13 , administration of the vascular MMP-9 inhibitor prevents injury from ischemia or reperfusion to a tissue selected from a brain, a liver, a limb, a heart, or a combination thereof.