Normobaric Hyperoxia Reduces the Neurovascular Complications Associated With Delayed Tissue Plasminogen Activator Treatment in a Rat Model of Focal Cerebral Ischemia

Abstract

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. 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. 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. Our results suggest that early normobaric hyperoxia treatment may represent an important strategy to increase the safety of delayed tPA thrombolysis in ischemic stroke.