Normobaric hyperoxia reduces the neurovascular complications associated with delayed tissue plasminogen activator treatment in a rat model of focal cerebral ischemia.
OBJECTIVE
A major limitation of tissue plasminogen activator (tPA) thrombolysis for ischemic stroke is the narrow time window for safe and effective therapy. Delayed tPA thrombolysis increases the risk of cerebral hemorrhage and mortality, which, in part, is related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). We recently showed that normobaric hyperoxia treatment reduces MMP-9 expression and blood-brain barrier disruption in the ischemic brain. Therefore, we hypothesized that normobaric hyperoxia could increase the safety of delayed tPA thrombolysis in stroke.


METHODS
Male Sprague-Dawley rats were exposed to normobaric hyperoxia (95% O(2)) or normoxia (21% O(2)) during 5-hour filament occlusion of the middle cerebral artery followed by 19-hour reperfusion. Thirty minutes before reperfusion, saline or tPA was continuously infused to rats over 1 hour. Outcome parameters were neurological score, mortality rate, brain edema, hemorrhage volume, and MMP-9. Hemorrhage was quantified with a hemoglobin spectrophotometry method. Edema was evaluated as hemispheric enlargement. MMP-9 was measured by gelatin zymography.


RESULTS
In normoxic rats, delayed tPA treatment at 4.5 hours after stroke onset resulted in high mortality, more severe neurological deficits, increased hemorrhage volumes, and augmented MMP-9 induction compared with saline. Rats treated with combined normobaric hyperoxia and tPA showed significantly reduced tPA-associated mortality, brain edema, hemorrhage, and MMP-9 augmentation as compared with tPA alone.


CONCLUSIONS
Our results suggest that early normobaric hyperoxia treatment may represent an important strategy to increase the safety of delayed tPA thrombolysis in ischemic stroke.
Liu
Wenlan
W
College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA. kliu@salud.unm.edu
Hendren
Jill
J
Qin
Xu-Jun
XJ
Liu
Ke Jian
KJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000378:metabolism / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D002543:Cerebral Hemorrhage / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D018496:Hyperoxia / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9