119: PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Abstract

Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumor necrosis factor alpha (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages [1] and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischemia/reperfusion (I/R) models of stroke. In vitro , restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia – an effect that is sensitive to PI3Kd inhibition. In vivo , transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110dD910A/D910A) or wild-type mice pre- or post-treated with thePI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischemic stroke [2] .