Lee Hsueh-Te, Chang Ying-Chao, Wang Lin-Yu, Wang Shan-Tair, Huang Chao-Ching, Ho Chien-Jung
Institute of Basic Medical Science, Medical College, National Cheng Kung University, Tainan, Taiwan.
Ann Neurol. 2004 Nov;56(5):611-23. doi: 10.1002/ana.20259.
Perinatal hypoxic-ischemic (HI) brain injury is a major cause of permanent neurological dysfunction in children. An approach to study the treatment of neonatal HI encephalopathy that allows for neuroprotection is to investigate the states of tolerance to HI. Twenty-four-hour carotid-artery ligation preconditioning established by delaying the onset of hypoxia for 24 hours after permanent unilateral carotid ligation rats markedly diminished the cerebral injury, however, the signaling mechanisms of this carotid-artery ligation preconditioning in neonatal rats remain unknown. Ligation of the carotid artery 24 hours before hypoxia provided complete neuroprotection and produced improved performance on the Morris water maze compared with ligation performed 1 hour before hypoxia. Carotid artery ligation 6 hours before hypoxia produced intermediate benefit. The 24-hour carotid-artery ligation preconditioning was associated with a robust and sustained activation of a transcription factor, the cAMP response element-binding protein (CREB), on its phosphorylation site on Ser133. Intracerebroventricular infusions of antisense CREB oligodeoxynucleotides significantly reduced the 24-hour carotid-artery ligation-induced neuroprotection effects by decreasing CREB expressions. Pharmacological activation of the cAMP-CREB signaling with rolipram 24 hours before hypoxia protected rat pups at behavioral and pathological levels by sustained increased CREB phosphorylation. This study suggests that 24-hour carotid-artery ligation preconditioning provides important mechanisms for potential pharmacological preconditioning against neonatal HI brain injury.
围产期缺氧缺血性（HI）脑损伤是儿童永久性神经功能障碍的主要原因。一种研究新生儿HI脑病治疗方法并实现神经保护的途径是研究对HI的耐受状态。通过在永久性单侧颈动脉结扎大鼠后延迟缺氧发作24小时建立的24小时颈动脉结扎预处理显著减轻了脑损伤，然而，这种颈动脉结扎预处理在新生大鼠中的信号传导机制仍然未知。与在缺氧前1小时进行结扎相比，在缺氧前24小时结扎颈动脉可提供完全的神经保护，并在莫里斯水迷宫实验中表现出更好的成绩。在缺氧前6小时结扎颈动脉产生了中等程度的益处。24小时颈动脉结扎预处理与转录因子cAMP反应元件结合蛋白（CREB）在其丝氨酸133磷酸化位点的强烈且持续的激活有关。脑室内注入反义CREB寡脱氧核苷酸通过降低CREB表达显著降低了24小时颈动脉结扎诱导的神经保护作用。在缺氧前24小时用咯利普兰对cAMP-CREB信号进行药理学激活，通过持续增加CREB磷酸化，在行为和病理水平上保护了幼鼠。这项研究表明，24小时颈动脉结扎预处理为针对新生儿HI脑损伤的潜在药理学预处理提供了重要机制。
