Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion
Neuroprotective impact of prothymosin alpha-derived hexapeptide against retinal ischemia–reperfusion
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DOI：
10.1016/j.neuroscience.2016.01.007
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发表时间：
2016-03
期刊：
影响因子：
3.3
通讯作者：
H. Ueda;Sebok Kumar Halder (PhD);H. Matsunaga;K. Sasaki;S. Maeda
中科院分区：
文献类型：
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作者：
H. Ueda;Sebok Kumar Halder (PhD);H. Matsunaga;K. Sasaki;S. Maeda
前胸腺素α（ProTα）对脑和视网膜缺血或血清饥饿应激具有鲁棒性作用。在ProTα序列中，活性核心30-氨基酸肽/P30（a.a.49-78）对于抗缺血的原始神经保护作用是必需的。此外，P30中的9-氨基酸肽序列/P9（a.a.52-60）仍然显示针对脑和视网膜缺血的神经保护活性，尽管P9不如P30有效。由于以前对ProTα结构-活性关系的研究还不够充分，因此任何小于P9的序列都有可能保留有效的神经保护活性。当在小鼠视网膜缺血后24小时玻璃体内注射不同的P9-和P30-相关肽时，6-氨基酸肽/P6（NEVDEE，a.a.51-56）显示针对缺血诱导的视网膜功能缺陷的有效保护作用，其在视网膜电图（ERG）中与P30肽的水平和在苏木精和伊红（HE）染色中的组织学损伤等效。使用ERG和HE染色的进一步研究表明，玻璃体内或静脉内（i. v.）注射修饰的P6肽/P6 Q（NEVDQE）有效地抑制视网膜缺血诱导的功能和组织学损伤。在免疫组化分析中，缺血诱导的视网膜神经节细胞，双极细胞，无长突细胞和感光细胞的损失被抑制的全身管理与P6 Q肽缺血应激后24小时。此外，P6 Q肽的系统性后处理显著抑制视网膜缺血诱导的小胶质细胞和星形胶质细胞活化，分别增加离子化钙结合衔接分子1（Iba-1）和胶质细胞酸性蛋白（GFAP）的强度，以及它们的形态学变化，增加数量和迁移。因此，本研究证实了ProTα中6-氨基酸肽（P6）衍生的修饰P6肽P6 Q（NEVDQE）对缺血性损伤的治疗意义。
Prothymosin alpha (ProTα) has robustness roles against brain and retinal ischemia or serum-starvation stress. In the ProTα sequence, the active core 30-amino acid peptide/P30(a.a.49–78) is necessary for the original neuroprotective actions against ischemia. Moreover, the 9-amino acid peptide sequence/P9(a.a.52–60) in P30still shows neuroprotective activity against brain and retinal ischemia, though P9is less potent than P30. As the previous structure–activity relationship study for ProTα may not be enough, the possibility still exists that any sequence smaller than P9retains potent neuroprotective activity. When different P9- and P30-related peptides were intravitreally injected 24 h after retinal ischemia in mice, the 6-amino acid peptide/P6(NEVDEE, a.a.51–56) showed potent protective effects against ischemia-induced retinal functional deficits, which are equipotent to the level of P30peptide in electroretinography (ERG) and histological damage in Hematoxylin and Eosin (HE) staining. Further studies using ERG and HE staining suggested that intravitreal or intravenous (i.v.) injection with modified P6peptide/P6Q (NEVDQE) potently inhibited retinal ischemia-induced functional and histological damage. In an immunohistochemical analysis, the ischemia-induced loss of retinal ganglion, bipolar, amacrine and photoreceptor cells were inhibited by a systemic administration with P6Q peptide 24 h after the ischemic stress. In addition, systemic post-treatment with P6Q peptide significantly inhibited retinal ischemia-induced microglia and astrocyte activation in terms of increased ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) intensity, respectively, as well as their morphological changes, increased number and migration. Thus, this study demonstrates the therapeutic significance of modified P6peptide P6Q (NEVDQE) derived from 6-amino acid peptide (P6) in ProTα against ischemic damage.