A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations.
A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations.
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DOI：
10.1016/j.neuroscience.2009.09.049
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发表时间：
2009-12-29
期刊：
影响因子：
3.3
通讯作者：
Aiso, S.
中科院分区：
文献类型：
--
作者：
Sari, Y.;Chiba, T.;Yamada, M.;Rebeca, G. V.;Aiso, S.
已知胎儿酒精暴露会通过细胞凋亡诱导细胞死亡。我们发现 Colivelin (CLN) 是一种具有 SALLRSIPAPAGASRLLLLTGEIDLP 序列的新型肽，可以防止这种细胞凋亡。我们的初步实验表明，CLN 增强了暴露于酒精的初级皮质神经元的活力。然后，我们使用胎儿酒精暴露的小鼠模型来确定这些神经保护作用背后的细胞内机制。在胚胎第 7 天 (E7)，体重匹配的怀孕雌性被分配到以下组：(1) 乙醇液体饮食 (ALC) 25% (4.49%，v/v) 乙醇衍生热量； (2)双馈控制； (3) 正常饮食； (4) ALC联合CLN(20μg/20g体重)给药(腹腔注射)； (5)配对喂养并联合施用(腹腔注射)CLN(20μg/20g体重)。 E13时，收集胎儿大脑并进行TUNEL染色、caspase-3比色测定、ELISA和MSD电化学发光分析。 CLN 阻断酒精引起的脑重量下降，并防止酒精引起的：细胞凋亡、caspase-3 的激活和胞浆细胞色素 c 的增加以及线粒体细胞色素 c 的减少。对上游信号通路中蛋白质的分析表明，CLN 下调 c-Jun N 末端激酶的磷酸化。此外，CLN 还可防止酒精引起的 BAD 蛋白磷酸化减少。因此，CLN 似乎直接作用于上游信号蛋白，以防止酒精诱导的细胞凋亡。对这些蛋白质及其信号传导机制的进一步评估可能会促进神经保护疗法的发展。
Fetal alcohol exposure is known to induce cell death through apoptosis. We found that colivelin (CLN), a novel peptide with the sequence SALLRSIPAPAGASRLLLLTGEIDLP, prevents this apoptosis. Our initial experiment revealed that CLN enhanced the viability of primary cortical neurons exposed to alcohol. We then used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying these neuroprotective effects. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet (ALC) 25% (4.49%, v/v) ethanol derived calories; (2) pair-fed control; (3) normal chow; (4) ALC combined with administration (i.p.) of CLN (20 μg/20 g body weight); and (5) pair-fed combined with administration (i.p.) of CLN (20 μg/20 g body weight). On E13, fetal brains were collected and assayed for TUNEL staining, caspase-3 colorimetric assay, ELISA, and MSD electrochemiluminescence. CLN blocked the alcohol-induced decline in brain weight and prevented alcohol-induced: apoptosis, activation of caspase-3 and increases of cytosolic cytochrome c, and decreases of mitochondrial cytochrome c. Analysis of proteins in the upstream signaling pathway revealed that CLN down-regulated the phosphorylation of the c-Jun N-terminal kinase. Moreover, CLN prevented alcohol-induced reduction in phosphorylation of BAD protein. Thus, CLN appears to act directly on upstream signaling proteins to prevent alcohol-induced apoptosis. Further assessment of these proteins and their signaling mechanisms is likely to enhance development of neuroprotective therapies.
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