title: Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation.
abstract: OBJECTIVE
  Hypoxic preconditioning (PC) confers robust neuroprotection against neonatal hypoxic-ischemic brain injury (H-I), yet the underlying mechanism is poorly understood. In the adult brain, neuronal survival after ischemia is associated with the activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway. Suppression of inflammation is a newly identified direct consequence of PI3-K/Akt signaling. We therefore investigated whether PI3-K/Akt suppresses inflammation and contributes to PC-induced neuroprotection.
  
  
  METHODS
  Postnatal day 7 rats were exposed for 3 hours to either ambient air or 8% oxygen, which induces hypoxic PC. H-I was produced 24 hours later by unilateral carotid artery ligation followed by 2.5 hours of hypoxia. Animals were euthanized 0 to 24 hours later for detecting Akt and glycogen synthetase kinase-3beta phosphorylation (p-Akt, p-GSK-3beta), 24 hours later for assessing cytokine expression and inflammatory markers, and 7 days later for measuring brain tissue loss. In addition, LY294002 was injected intracerebroventricularly to inhibit PI3-K/Akt.
  
  
  RESULTS
  Brains with H-I without PC showed delayed but sustained reduction in p-Akt. PC restored the levels of p-Akt and the Akt substrate GSK-3beta, reduced proinflammatory markers (NF-kappaB, COX-2, CD68, myeloperoxidase, and microglial activation), and markedly ameliorated H-I-induced brain tissue loss. Inhibition of PI3-K/Akt using LY294002 attenuated PC neuroprotection and promoted the expression of NF-kappaB, COX-2, and CD68. Proteomic microarray analysis revealed that PC inhibited expression of proinflammatory cytokines induced by H-I or a dose of lipopolysaccharide that resulted in minimal tissue damage.
  
  
  CONCLUSIONS
  Suppression of inflammatory responses may contribute to PC neuroprotection against neonatal H-I brain injury. This effect is mediated in part via upregulating PI3-K/Akt activity.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.forename: Armando P
authors.initials: AP
authors.lastname: Signore
authors.forename: Masanori
authors.initials: M
authors.lastname: Iwai
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johnnides
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hickey
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004789:Enzyme Activation / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control*; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control; D019194:Ischemic Preconditioning / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt