title: Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway.
abstract: OBJECTIVE
  Remote ischemic postconditoning, a phenomenon in which brief ischemic stimuli of 1 organ protect another organ against an ischemic insult, has been demonstrated to protect the myocardium and adult brain in animal models. However, mediators of the protection and underlying mechanisms remain to be elucidated. In the present study, we tested the hypothesis that remote limb ischemic postconditioning applied immediately after hypoxia provides neuroprotection in a rat model of neonatal hypoxia-ischemia (HI) by mechanisms involving activation of the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.
  
  
  METHODS
  HI was induced in postnatal Day 10 rat pups by unilateral carotid ligation and 2 hours of hypoxia. Limb ischemic postconditioning was induced by 4 conditioning cycles of 10 minutes of ischemia and reperfusion on both hind limbs immediately after HI. The opioid antagonist naloxone, phosphatidylinositol-3-kinase inhibitor wortmannin, or opioid agonist morphine was administered to determine underlying mechanisms. Infarct volume, brain atrophy, and neurological outcomes after HI were evaluated. Expression of phosphorylated Akt, Bax, and phosphorylated ERK1/2 was determined by Western blotting.
  
  
  RESULTS
  Limb ischemic postconditioning significantly reduced infarct volume at 48 hours and improved functional outcomes at 4 weeks after HI. Naloxone and wortmannin abrogated the postconditioning-mediated infarct-limiting effect. Morphine given immediately after hypoxia also decreased infarct volume. Furthermore, limb ischemic postconditioning recovered Akt activity and decreased Bax expression, whereas no differences in phosphorylated ERK1/2expression were observed.
  
  
  CONCLUSIONS
  Limb ischemic postconditioning protects against neonatal HI brain injury in rats by activating the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.
authors.affiliation: Department of Physiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Nancy
authors.initials: N
authors.lastname: Fathali
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.forename: Robert P
authors.initials: RP
authors.lastname: Ostrowski
authors.forename: Chunhua
authors.initials: C
authors.lastname: Chen
authors.forename: Robert D
authors.initials: RD
authors.lastname: Martin
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D006614:Hindlimb / Q000098:blood supply*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000517:prevention & control*; D007511:Ischemia / Q000378:metabolism / Q000517:prevention & control; D057775:Ischemic Postconditioning / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011957:Receptors, Opioid; D051057:Proto-Oncogene Proteins c-akt