PI3Kγ (Phosphoinositide 3-Kinase-γ) Inhibition Attenuates Tissue-Type Plasminogen Activator-Induced Brain Hemorrhage and Improves Microvascular Patency after Embolic Stroke

Abstract

Genetic and pharmacological inhibition of the PI3Kγ (phosphoinositide 3-kinase-γ) exerts anti-inflammatory and protective effects in a number of inflammatory and autoimmune diseases. SHRs (spontaneously hypertensive rats) subjected to embolic middle cerebral occlusion were treated with AS605240 (30 mg/kg) at 2 or 4 hours, tPA (tissue-type plasminogen activator; 10 mg/kg) at 2 or 6 hours, or AS605240 at 4 hours plus tPA at 6 hours. Infarct volume, brain hemorrhage, neurological function, microvascular thrombosis, and cerebral microvessel patency were examined. We found that treatment with AS605240 alone at 2 hours or the combination treatment with AS605240 at 4 hours and tPA at 6 hours significantly reduced infarct volume and neurological deficits at 3 days after stroke compared with ischemic rats treated with saline, AS605240 alone at 4 hours, and tPA alone at 6 hours. Moreover, the combination treatment effectively prevented the delayed tPA-induced cerebral hemorrhage. These protective effects are associated with reduced disruption of the blood-brain barrier, reduced downstream microvascular thrombosis, and improved microvascular patency by AS605240. Inhibition of the NF-κB (nuclear transcription factor-κB)-dependent MMP (matrix metalloproteinase)-9 and PAI-1 (plasminogen activator inhibitor-1) in the ischemic brain endothelium may underlie the neurovascular protective effect of AS605240. In addition, the combination treatment significantly reduced circulating platelet P-selectin expression and platelet-leukocyte aggregation compared with ischemic rats treated with saline or tPA alone at 6 hours. In conclusion, inhibition of PI3Kγ with AS605240 reduces delayed tPA-induced intracerebral hemorrhage and improves microvascular patency, which likely contributes to neuroprotective effect of the combination treatment.