The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential
The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential
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DOI：
10.1210/en.2005-1038
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Miyashita, K;Itoh, H;Nakao, K
主要来源于血管壁，在脑卒中后表达明显增强。我们已经发现，AM不仅促进血管舒张，而且促进血管再生。在这项研究中，我们专注于AM在缺血性脑中的作用，并检查其治疗潜力。我们开发了新的AM转基因（AM-Tg）小鼠，在肝脏中过量产生AM，并进行大脑中动脉闭塞20分钟（20 mMCAO），以检查AM对缺血性脑的退行性或再生过程的影响。AM-Tg小鼠20 m-MCAO后梗死面积和胶质增生减少，与缺血核心中白细胞浸润、氧化应激和凋亡的抑制有关。此外，在AM-Tg小鼠中，血管再生和随后的神经发生得到增强，之前是CD 34（+）单核细胞动员的增加，其可以分化为内皮细胞。在AM-Tg小鼠中观察到的血管神经再生作用与神经保护作用相结合导致运动功能恢复改善。AM-Tg小鼠的脑水肿也通过抑制血管通透性而显著减少。在体外，AM对神经元细胞具有直接的抗凋亡和神经发生作用。外源性AM也能缩小缺血20 m-MCAO小鼠的梗死面积，促进血管再生和功能恢复。综上所述，本研究提示了AM的神经保护和血管神经再生作用，并为通过其多种激素作用挽救缺血脑的新策略提供了基础。
mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20mMCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34(+) mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.