Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation

• Published in: Stroke (1970) 2007-03, Vol.38 (3), p.1017-1024
• Main Authors: WEI YIN, SIGNORE, Armando P, IWAI, Masanori, GUODONG CAO, YANQIN GAO, JOHNNIDES, Michael J, HICKEY, Robert W, JUN CHEN
• Format: Article
• Language: English
• Subjects: Anesthetics. Neuromuscular blocking agents; Animals; Animals, Newborn; Biological and medical sciences; Enzyme Activation - physiology; Hypoxia-Ischemia, Brain - enzymology; Hypoxia-Ischemia, Brain - pathology; Hypoxia-Ischemia, Brain - prevention & control; Inflammation - enzymology; Inflammation - prevention & control; Ischemic Preconditioning - methods; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - biosynthesis; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt - biosynthesis; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-akt - physiology; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/01.STR.0000258102.18836.ca

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. 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. 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. 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.