Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway.
Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway.
复制标题
DOI：
10.1161/strokeaha.110.592162
复制
发表时间：
2011-02
期刊：
影响因子：
8.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Zhou Y;Fathali N;Lekic T;Ostrowski RP;Chen C;Martin RD;Tang J;Zhang JH
远端缺血后适应是一种对一个器官进行短暂的缺血刺激以保护另一个器官免受缺血损伤的现象，在动物模型中已被证明可以保护心肌和成人大脑。然而，保护的介质和潜在的机制仍有待阐明。在本研究中，我们通过激活阿片受体/磷脂酰肌醇-3激酶/Akt信号通路的机制，验证了缺氧后立即进行远端肢体缺血后适应对新生儿缺氧缺血（HI）大鼠模型的神经保护作用。通过单侧颈动脉结扎和缺氧2小时诱导出生后第10天大鼠幼崽HI。在HI后立即对双后肢进行10分钟的缺血再灌注4次调节循环，诱导肢体缺血后适应。阿片拮抗剂纳洛酮、磷脂酰肌醇-3激酶抑制剂wortmannin或阿片激动剂吗啡被用于确定潜在的机制。评估HI后的梗死体积、脑萎缩和神经预后。Western blotting检测磷酸化Akt、Bax和磷酸化ERK1/2的表达。肢体缺血后适应在48小时内显著减少梗死体积，并在HI后4周改善功能结局。纳洛酮和沃特曼宁消除了调节后介导的梗死限制作用。缺氧后立即给予吗啡也能减少梗死体积。此外，肢体缺血后适应恢复了Akt活性，降低了Bax表达，而磷酸化的erk1 /2表达没有差异。肢体缺血后适应通过激活阿片受体/磷脂酰肌醇-3激酶/Akt信号通路保护大鼠新生儿HI脑损伤。
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. 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. 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. Limb ischemic postconditioning protects against neonatal HI brain injury in rats by activating the opioid receptor/phosphatidylinositol-3-kinase/Akt signaling pathway.