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.

我们之前的研究表明，AS605240 与标准大鼠剂量 tPA (10 mg/kg) 组合的 PI3Kγ 抑制作用可减轻大鼠缺血性中风后 3 天迟发性 tPA 诱导的脑出血并改善急性中风损伤。本研究的目的是探讨AS605240与tPA联合是否可以增强溶栓疗效，从而可以应用较低剂量的tPA来改善缺血性中风后的长期预后。结果显示，与单独使用生理盐水、AS605240或小剂量tPA组相比，卒中发病后4小时AS605240加低剂量tPA（5 mg/kg）联合治疗显着减少了卒中后24小时的梗塞体积和神经功能缺损。重要的是，联合疗法显着减少了迟发性 tPA 相关脑出血。此外，与单独使用盐水和 tPA 相比，联合治疗显着减少了大脑中动脉内残留栓子的大小，这与血浆纤溶酶原激活剂抑制剂-1 (PAI-1) 活性降低有关。最后，与盐水治疗组相比，AS605240 加低剂量 tPA 组合改善了中风后至少 35 天的长期结果。总而言之，这些发现表明，用 AS605240 抑制 PI3Kγ 可能作为增强 tPA 在急性缺血性中风中溶栓疗效的辅助方法。