| First Author | Low PC | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 3450 | PubMed ID | 24625684 |
| Mgi Jnum | J:210223 | Mgi Id | MGI:5569837 |
| Doi | 10.1038/ncomms4450 | Citation | Low PC, et al. (2014) PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nat Commun 5:3450 |
| abstractText | 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 ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kdelta) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kdelta inhibition confers protection in ischaemia/reperfusion 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 PI3Kdelta inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kdelta (p110delta(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kdelta inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kdelta as a potential therapeutic target in ischaemic stroke. |
