PI3K delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Low, Pei Ching, Manzanero, Silvia, Mohannak, Nika, Narayana, Vinod K., Nguyen, Tam H., Kvaskoff, David, Brennan, Faith H., Ruitenberg, Marc J., Gelderblom, Mathias, Magnus, Tim, Kim, Hyun Ah, Broughton, Brad R. S., Sobey, Christopher G., Vanhaesebroeck, Bart, Stow, Jennifer L., Arumugam, Thiruma V. and Meunier, Frédéric A. (2014) PI3K delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nature Communications, 5 3450: 1-12. doi:10.1038/ncomms4450

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Author Low, Pei Ching
Manzanero, Silvia
Mohannak, Nika
Narayana, Vinod K.
Nguyen, Tam H.
Kvaskoff, David
Brennan, Faith H.
Ruitenberg, Marc J.
Gelderblom, Mathias
Magnus, Tim
Kim, Hyun Ah
Broughton, Brad R. S.
Sobey, Christopher G.
Vanhaesebroeck, Bart
Stow, Jennifer L.
Arumugam, Thiruma V.
Meunier, Frédéric A.
Title PI3K delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
Formatted title
PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2014-03-14
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ncomms4450
Open Access Status File (Publisher version)
Volume 5
Issue 3450
Start page 1
End page 12
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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 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 (PI3Kδ) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kδ 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 PI3Kδ inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kδ (p110δD910A/D910A) or wild-type mice pre- or post-treated with the PI3Kδ inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kδ as a potential therapeutic target in ischaemic stroke.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 1005964
Institutional Status UQ

 
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Created: Wed, 26 Mar 2014, 22:01:25 EST by Faith Reece on behalf of Queensland Brain Institute