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

The whole basis of Dr. Tobinicks use of etanercept is to interfere with TNF. Whom will do the followup research on this? This will never be followed up since we have NO stroke leadership we can bring these simple questions to. Every stroke survivor for the next 50 years is going to be screwed because nothing is going to get done until WE take over all the stroke associations.
If Dr. Tobinick cared at all about proving if his ideas are correct he would have followed up this research from March 2014 with clinical research trials.
http://www.nature.com/ncomms/2014/140314/ncomms4450/full/ncomms4450.html 

• Pei Ching Low,
• Silvia Manzanero,
• Nika Mohannak,
• Vinod K. Narayana,
• Tam H. Nguyen,
• David Kvaskoff,
• Faith H. Brennan,
• Marc J. Ruitenberg,
• Mathias Gelderblom,
• Tim Magnus,
• Hyun Ah Kim,
• Brad R. S. Broughton,
• Christopher G. Sobey,
• Bart Vanhaesebroeck,
• Jennifer L. Stow,
• Thiruma V. Arumugam
• & Frédéric A. Meunier

• Affiliations
• Contributions
• Corresponding authors

Nature Communications

5,

Article number:

3450

doi:10.1038/ncomms4450

Received

05 December 2013

Accepted

13 February 2014

Published

14 March 2014

Article tools

• Citation
• Reprints
• Rights & permissions
• Article metrics

Abstract

• Abstract•
• References•
• Author information•
• Supplementary information

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 (p110δ^D910A/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.