Remote Limb Ischemic Postconditioning Protects Against Neonatal Hypoxic-Ischemic Brain Injury in Rat Pups by the Opioid Receptor/Akt Pathway

被引:98
作者
Zhou, Yilin [1 ]
Fathali, Nancy [2 ]
Lekic, Tim [2 ]
Ostrowski, Robert P. [2 ]
Chen, Chunhua [2 ]
Martin, Robert D. [1 ]
Tang, Jiping [2 ]
Zhang, John H. [1 ,2 ,3 ]
机构
[1] Loma Linda Univ, Sch Med, Dept Anesthesiol, Loma Linda, CA 92354 USA
[2] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92354 USA
[3] Loma Linda Univ, Sch Med, Dept Neurosurg, Loma Linda, CA 92354 USA
基金
美国国家卫生研究院;
关键词
Akt; limb ischemic postconditioning; neonatal hypoxia-ischemia; opioid receptor; NEUROLOGICAL FUNCTION; CARDIOPROTECTION; NEUROPROTECTION; STROKE;
D O I
10.1161/STROKEAHA.110.592162
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and Purpose-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. (Stroke. 2011; 42: 439-444.)
引用
收藏
页码:439 / 444
页数:6
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