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(Stroke. 2007;38:1017.)
© 2007 American Heart Association, Inc.

Original Contributions

Preconditioning Suppresses Inflammation in Neonatal Hypoxic Ischemia Via Akt Activation

Wei Yin, MD, PhD; Armando P. Signore, PhD; Masanori Iwai, MD; Guodong Cao, PhD; Yanqin Gao, MD; Michael J. Johnnides, MS; Robert W. Hickey, MD Jun Chen, MD

From Department of Neurology (W.Y., A.P.S., M.I., G.C., M.J.J., R.W.H., J.C.) and Institute of Neurodegenerative Diseases (A.P.S., G.C., J.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; State Key Laboratory of Medical Neurobiology (G.C., Y.C., J.C.), Fudan University School of Medicine, Shanghai, China; Division of Pediatric Emergency Medicine (R.W.H.), Children’s Hospital of Pittsburgh, Pittsburgh, Pa; Geriatric Research (J.C.), Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pa.

Correspondence to Dr Jun Chen, Department of Neurology, S-507, Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213. E-mail chenj2{at}upmc.edu

Background and Purpose— 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-3ß phosphorylation (p-Akt, p-GSK-3ß), 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-3ß, reduced proinflammatory markers (NF-B, 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-B, 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.

Key Words: hypoxia-ischemia • inflammation • neonatal • p-Akt • preconditioning

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