CRUCIAL ROLE FOR Ser133-PHOSPHORYLATED FORM OF CYCLIC AMP-RESPONSIVE ELEMENT BINDING PROTEIN SIGNALING IN THE DIFFERENTIATION AND SURVIVAL OF NEURAL PROGENITORS UNDER CHRONIC CEREBRAL HYPOPERFUSION
CRUCIAL ROLE FOR Ser133-PHOSPHORYLATED FORM OF CYCLIC AMP-RESPONSIVE ELEMENT BINDING PROTEIN SIGNALING IN THE DIFFERENTIATION AND SURVIVAL OF NEURAL PROGENITORS UNDER CHRONIC CEREBRAL HYPOPERFUSION
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DOI：
10.1016/j.neuroscience.2009.05.004
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发表时间：
2009-08-18
期刊：
影响因子：
3.3
通讯作者：
Urabe, T.
中科院分区：
文献类型：
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作者：
Miyamoto, N.;Tanaka, R.;Urabe, T.
各种刺激，如缺血/缺氧，提高了新生细胞在脑室下区的存活率，并以切向链状向嗅球迁移。本研究评估了慢性脑低灌流条件下新生神经元从脑室下区到嗅球的命运，并使用III型磷酸二酯酶的有效抑制剂西洛他唑，研究了cAMP反应元件结合蛋白信号在这些神经元存活中的作用。结扎大鼠双侧颈总动脉。随机分为假手术组(n=70)、赋形剂组(n=70)和III型磷酸二酯酶抑制剂治疗组(n=70)。分别于低灌流后第7、14、21、28天取脑组织行5-溴脱氧尿苷免疫组织化学染色及一系列神经元和胶质细胞标志物分析。赋形剂组大鼠嗅球体积逐渐缩小(P<；0.05)，而假手术组和III型磷酸二酯酶抑制剂治疗组嗅球缩小不明显。与假手术组大鼠相比，低灌注组大鼠室下区新生神经母细胞数量显著增多(P<；0.05)，而吻侧游走流和嗅球的新生神经母细胞数量显著减少(P<；0.05)。用III型磷酸二酯酶抑制剂处理的大鼠神经母细胞数量增加，细胞存活和分化增强(P<；0.05)。在给药组大鼠的脑室下区、吻部迁移流和嗅球中，神经母细胞内的磷酸化cAMP反应元件结合蛋白显著减少(P<；0.05)，但用III型磷酸二酯酶抑制剂治疗后，这种表达在整个低灌流过程中恢复，导致神经再生增强(P<；0.05)。这些作用可被蛋白激酶A和C抑制剂所消除。我们的结果表明，cAMP反应元件结合蛋白信号是长时间低灌流后神经发生的关键介质，为缺血性脑损伤的新的再生治疗提供了基础。(C)2009年IBRO。爱思唯尔有限公司出版。保留所有权利。
Various stimuli, such as ischemia/hypoxia enhance newborn cell survival in the subventricular zone and their migration tangentially in chains toward the olfactory bulb. The present study assessed the fate of newborn neurons from subventricular zone to olfactory bulb under conditions of chronic cerebral hypoperfusion, and examined the role of cAMP-responsive element binding protein signaling on the survival of these neurons by using cilostazol, a potent inhibitor of type III phosphodiesterase. Rats underwent bilateral common carotid artery ligation. They were divided into sham-operated (n=70), vehicle- (n=70), and type III phosphodiesterase inhibitor-treated (n=70) groups. Immunohistochemically-stained section for 5-bromodeoxyuridine and a series of neuronal and glial markers were analyzed at days 7, 14, 21 and 28 after hypoperfusion. The reduction of olfactory bulb size gradually progressed in the vehicle group (P < 0.05), but not in the sham-operated and type III phosphodiesterase inhibitor-treated group. The subventricular zone of the vehicle-treated rats contained significantly larger numbers of newborn neuroblasts after hypoperfusion, compared with sham-operated rats (P < 0.05), but significantly lower numbers in the rostral migratory stream and olfactory bulb (P < 0.05). Treatment of rats with type III phosphodiesterase inhibitor increased the number of neuroblasts and enhanced the survival and differentiation of cells (P < 0.05). Phosphorylated cAMP-responsive element binding protein within neuroblasts was markedly decreased in the subventricular zone, rostral migratory stream, and olfactory bulb of vehicle-treated rats (P < 0.05), but treatment with type III phosphodiesterase inhibitor resulted in recovery of this expression throughout hypoperfusion, leading to enhanced neurogenesis (P < 0.05). These effects were abrogated by protein kinase A and C inhibitor. Our results indicated that cAMP-responsive element binding protein signaling is a key mediator of neurogenesis after prolonged hypoperfusion and provide the basis for new regenerative therapies for ischemic brain injury. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.