Institute of Molecular Genetics of National Research Center "Kurchatov Institute", Kurchatov Sq. 2, 123182 Moscow, Russia.
Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, 119991 Moscow, Russia.
Int J Mol Sci. 2021 Sep 17;22(18):10054. doi: 10.3390/ijms221810054.
Natural melanocortins (MCs) have been used in the successful development of drugs with neuroprotective properties. Here, we studied the behavioral effects and molecular genetic mechanisms of two synthetic MC derivatives-ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP under normal and acute restraint stress (ARS) conditions. Administration of Semax or ACTH(6-9)PGP (100 μg/kg) to rats 30 min before ARS attenuated ARS-induced behavioral alterations. Using high-throughput RNA sequencing (RNA-Seq), we identified 1359 differentially expressed genes (DEGs) in the hippocampus of vehicle-treated rats subjected to ARS, using a cutoff of >1.5 fold change and adjusted -value () < 0.05, in samples collected 4.5 h after the ARS. Semax administration produced > 1500 DEGs, whereas ACTH(6-9)PGP administration led to <400 DEGs at 4.5 h after ARS. Nevertheless, ~250 overlapping DEGs were identified, and expression of these DEGs was changed unidirectionally by both peptides under ARS conditions. Modulation of the expression of genes associated with biogenesis, translation of RNA, DNA replication, and immune and nervous system function was produced by both peptides. Furthermore, both peptides upregulated the expression levels of many genes that displayed decreased expression after ARS, and vice versa, the MC peptides downregulated the expression levels of genes that were upregulated by ARS. Consequently, the antistress action of MC peptides may be associated with a correction of gene expression patterns that are disrupted during ARS.
天然黑色素细胞（MCs）已被用于成功开发具有神经保护特性的药物。在这里，我们研究了两种合成 MC 衍生物-ACTH（4-7）PGP（Semax）和 ACTH（6-9）PGP 在正常和急性束缚应激（ARS）条件下的行为效应和分子遗传机制。在 ARS 前 30 分钟给大鼠施用 Semax 或 ACTH（6-9）PGP（100μg/kg）可减轻 ARS 引起的行为改变。使用高通量 RNA 测序（RNA-Seq），我们在接受 ARS 的载体处理的大鼠海马体中鉴定出 1359 个差异表达基因（DEG），使用 >1.5 倍变化的截止值和调整的 - 值（）<0.05，在 ARS 后 4.5 小时收集的样品中。Semax 给药产生了 >1500 个 DEG，而 ACTH（6-9）PGP 给药在 ARS 后 4.5 小时导致 <400 个 DEG。然而，鉴定出了约 250 个重叠的 DEG，并且这些 DEG 的表达在 ARS 条件下被两种肽都单向改变。两种肽都调节与生物发生、RNA 翻译、DNA 复制以及免疫和神经系统功能相关的基因的表达。此外，两种肽都上调了许多基因的表达水平，这些基因在 ARS 后表达下降，反之，MC 肽下调了 ARS 上调的基因的表达水平。因此，MC 肽的抗应激作用可能与纠正 ARS 期间破坏的基因表达模式有关。
