Our previous study showed that PI3Kγ inhibition with
AS605240 plus a standard rat-dose tPA (10 mg/kg) combination attenuates delayed tPA-induced
brain hemorrhage and ameliorates
acute stroke injury 3 days after
ischemic stroke in rats. The purpose of this study was to investigate whether combining
AS605240 with tPA can enhance thrombolytic efficacy, so that lower doses of tPA can be applied to improve long-term outcome after
ischemic stroke. The results showed that
AS605240 plus low-dose tPA (5 mg/kg) combination
therapy at 4 h after
stroke onset significantly reduced
infarct volume and neurological deficits at 24 h after
stroke compared with saline,
AS605240 or low-dose tPA alone group. Importantly, the combination
therapy significantly reduced the delayed tPA-associated
brain hemorrhage. Moreover, the combination
therapy significantly decreased the size of the residual
embolus within the middle cerebral artery, which was associated with a decrease in plasma
plasminogen activator inhibitor-1 (PAI-1) activity compared with saline and tPA alone. Finally,
AS605240 plus low-dose tPA combination improved long-term outcome for at least 35 days after
stroke compared with the saline-treated group. Taken together, these findings suggest that PI3Kγ inhibition with
AS605240 might act as an adjunct approach for enhancing tPA thrombolytic efficacy in
acute ischemic stroke.