Inhibition of PI3Kγ by AS605240 Plus Low-dose Tissue Plasminogen Activator (tPA) Combination Improves Thrombolytic Therapy in a Rat Model of Embolic Stroke

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.