Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain
Phosphodiesterase III inhibition promotes differentiation and survival of oligodendrocyte progenitors and enhances regeneration of ischemic white matter lesions in the adult mammalian brain
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DOI：
10.1038/jcbfm.2009.210
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发表时间：
2010-02-01
影响因子：
6.3
通讯作者：
Urabe, Takao
中科院分区：
文献类型：
--
作者：
Miyamoto, Nobukazu;Tanaka, Ryota;Urabe, Takao
血管性痴呆是由大脑供血受阻引起的，这导致缺血和随后的病变主要发生在白色物质中，这是该疾病的一个关键特征。在这项研究中，我们使用了慢性脑灌注不足大鼠模型，以表明再生的白色物质受损的低灌注是通过抑制磷酸二酯酶III增强。采用双侧颈总动脉结扎法制备慢性脑低灌注大鼠模型。在Morris水迷宫任务，溴脱氧尿苷，以及一系列的神经元和胶质细胞标记的免疫组化的性能进行了分析，直到28天后低灌注。在血管性痴呆患者和脑灌注不足的大鼠的大脑中，少突胶质细胞祖细胞的数量显著增加。少突胶质细胞祖细胞随后经历细胞死亡，少突胶质细胞的数量减少。在大鼠模型中，用磷酸二酯酶III抑制剂治疗可防止细胞死亡，显著增加成熟的少突胶质细胞，并促进白色物质的恢复和认知能力下降的恢复。磷酸二酯酶III抑制剂组应用蛋白激酶A/C抑制剂后，上述作用被抵消。我们的研究结果表明哺乳动物脑白色组织在缺血损伤后具有再生能力。Journal of Cerebral Blood Flow & Metabolism（2010）30，299-310; doi：10.1038/jcbfm.2009.210; 2009年10月14日在线发表
Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 299-310; doi: 10.1038/jcbfm.2009.210; published online 14 October 2009