title: Phosphatidylinositol-3-kinase gamma plays a central role in blood-brain barrier dysfunction in acute experimental stroke.
abstract: OBJECTIVE
  Phosphoinositide 3-kinase (PI3K)-γ is linked to inflammation and oxidative stress. This study was conducted to investigate the role of the PI3Kγ in the blood-brain barrier dysfunction and brain damage induced by focal cerebral ischemia/reperfusion.
  
  
  METHODS
  Wild-type and PI3Kγ knockout mice were subjected to middle cerebral artery occlusion (60 minutes) followed by reperfusion. Evans blue leakage, brain edema, infarct volumes, and neurological deficits were examined. Oxidative stress, neutrophil infiltration, and matrix metallopeptidase-9 were assessed. Activation of nuclear factor-κB and expression of proinflammatory and pro-oxidative genes were studied.
  
  
  RESULTS
  PI3Kγ deficiency significantly reduced blood-brain barrier permeability and brain edema formation, which were time-dependently correlated with preventing the degradation of the tight junction protein, claudin-5, and the basal lamina protein, collagen IV, and the phosphorylation of myosin light chain in brain microvessels. PI3Kγ deficiency suppressed ischemia/reperfusion-induced nuclear factor-κB p65 (Ser536) phosphorylation and the expression of the pro-oxidant enzyme NADPH oxidase (Nox1, Nox2, and Nox4) and proinflammatory adhesion molecules (E- and P-selectin, intercellular adhesion molecule-1) at different time points. These molecular changes were associated with significant inhibition of oxidative stress (superoxide production and malondialdehyde content), neutrophil infiltration, and matrix metallopeptidase-9 expression/activity in PI3Kγ knockout mice. Eventually, PI3Kγ deficiency significantly reduced infarct volumes and neurological scores at 24 hours after ischemia/reperfusion.
  
  
  CONCLUSIONS
  Our results provide the first direct demonstration that PI3Kγ plays a significant role in ischemia/reperfusion-induced blood-brain barrier disruption and brain damage. Future studies need to explore PI3Kγ as a potential target for stroke therapy.
authors.affiliation: Department of Neurosurgery, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.forename: Zifang
authors.initials: Z
authors.lastname: Song
authors.forename: Shiyong
authors.initials: S
authors.lastname: Yu
authors.forename: Abigail
authors.initials: A
authors.lastname: Piazza
authors.forename: Anil
authors.initials: A
authors.lastname: Nanda
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007249:Inflammation; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D015427:Reperfusion Injury; D020521:Stroke / Q000201:enzymology*
chemical_list: D016328:NF-kappa B; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D020780:Matrix Metalloproteinase 9