BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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: T Sasaki; J Irie-Sasaki; R G Jones; A J Oliveira-dos-Santos; W L Stanford; B Bolon; A Wakeham; A Itie; D Bouchard; I Kozieradzki; N Joza; T W Mak; P S Ohashi; A Suzuki; J M Penninger Journal: Science Date: 2000-02-11 Impact factor: 47.728
Authors: John Doukas; Wolfgang Wrasidlo; Glenn Noronha; Elena Dneprovskaia; Richard Fine; Sara Weis; John Hood; Anthony Demaria; Richard Soll; David Cheresh Journal: Proc Natl Acad Sci U S A Date: 2006-12-15 Impact factor: 11.205
Authors: R K Clark; E V Lee; C J Fish; R F White; W J Price; Z L Jonak; G Z Feuerstein; F C Barone Journal: Brain Res Bull Date: 1993 Impact factor: 4.077
Authors: Christoph Kleinschnitz; Henrike Grund; Kirstin Wingler; Melanie E Armitage; Emma Jones; Manish Mittal; David Barit; Tobias Schwarz; Christian Geis; Peter Kraft; Konstanze Barthel; Michael K Schuhmann; Alexander M Herrmann; Sven G Meuth; Guido Stoll; Sabine Meurer; Anja Schrewe; Lore Becker; Valérie Gailus-Durner; Helmut Fuchs; Thomas Klopstock; Martin Hrabé de Angelis; Karin Jandeleit-Dahm; Ajay M Shah; Norbert Weissmann; Harald H H W Schmidt Journal: PLoS Biol Date: 2010-09-21 Impact factor: 8.029
Authors: E Hirsch; V L Katanaev; C Garlanda; O Azzolino; L Pirola; L Silengo; S Sozzani; A Mantovani; F Altruda; M P Wymann Journal: Science Date: 2000-02-11 Impact factor: 47.728