Filippenkov Ivan B, Shpetko Yana Yu, Stavchansky Vasily V, Denisova Alina E, Gubsky Leonid V, Andreeva Lyudmila A, Myasoedov Nikolay F, Limborska Svetlana A, Dergunova Lyudmila V
Laboratory of Human Molecular Genetics, National Research Center "Kurchatov Institute", Kurchatov Sq. 2, 123182 Moscow, Russia.
Department of Biotechnology, Mendeleev University of Chemical Technology of Russia, Miusskaya Sq., 9, Building 1, 125047 Moscow, Russia.
Biomedicines. 2024 Dec 13;12(12):2830. doi: 10.3390/biomedicines12122830.
Ischemic stroke results from a disruption of cerebral blood flow. Adrenocorticotropic hormone (ACTH) serves as the basis for the creation of synthetic peptides as neuroprotective agents for stroke therapy. Previously, using RNA-Seq we first revealed differential expressed genes (DEGs) associated with ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP peptides under cerebral ischemia conditions. Analysis was carried out at 4.5 h after transient middle cerebral artery occlusion (tMCAO) model in the ipsilateral frontal cortex of a rat brain. Here, we analyzed the penumbra-associated frontal cortex of rats and actions under the same peptides at 24 h after tMCAO using RNA-Seq. 3774 DEGs (fold change > 1.5 and < 0.05) were identified under ischemia conditions, whereas 1539 and 2066 DEGs were revealed under Semax and ACTH(6-9)PGP peptides at 24 h after tMCAO. Furthermore, both peptides significantly reduced expression distortions caused by ischemia for 1171 genes associated with immune and neurosignaling pathways. Concomitantly, there were 32 DEGs under ACTH(6-9)PGP versus Semax administration at 24 h after tMCAO. Besides, neurogenesis-, angiogenesis-, protein kinase- and growth factor-related DEGs were revealed under peptides action. Previously, we observed the neuroprotective effect of peptides at the histological level in rat brains at 24 h after tMCAO. Thus, here we demonstrate the transcriptome manifestation of this histological effect. Furthermore, comparison with previous data at the 4.5 h post-tMCAO time point showed that the pattern of peptide action on the transcriptome depends on the time elapsed after tMCAO. We revealed that the effect of ACTH(6-9)PGP was more similar to Semax than different from it a day after tMCAO. At this time point, ACTH-like peptides compensated rat brain gene expression profiles disrupted by ischemia. Thus, our results may be useful for selecting more effective structures for future anti-stroke drugs and appropriate post-stroke time points for their testing.
缺血性中风是由脑血流中断引起的。促肾上腺皮质激素（ACTH）是合成肽作为中风治疗神经保护剂的基础。此前，我们使用RNA测序首次揭示了在脑缺血条件下与ACTH(4-7)PGP（赛美克斯）和ACTH(6-9)PGP肽相关的差异表达基因（DEG）。分析是在大鼠脑同侧额叶皮质的短暂大脑中动脉闭塞（tMCAO）模型后4.5小时进行的。在此，我们使用RNA测序分析了tMCAO后24小时大鼠与半暗带相关的额叶皮质以及相同肽作用下的情况。在缺血条件下鉴定出3774个DEG（倍数变化>1.5且<0.05），而在tMCAO后24小时，在赛美克斯和ACTH(6-9)PGP肽作用下分别揭示出1539个和2066个DEG。此外，两种肽均显著降低了与免疫和神经信号通路相关的1171个基因因缺血引起的表达畸变。同时，在tMCAO后24小时，ACTH(6-9)PGP与赛美克斯给药相比有32个DEG。此外，在肽作用下还揭示了与神经发生、血管生成、蛋白激酶和生长因子相关的DEG。此前，我们在tMCAO后24小时在大鼠脑的组织学水平上观察到了肽的神经保护作用。因此，在此我们展示了这种组织学效应的转录组表现。此外，与tMCAO后4.5小时的先前数据比较表明，肽对转录组的作用模式取决于tMCAO后经过的时间。我们发现，tMCAO一天后，ACTH(6-9)PGP的作用与赛美克斯更相似而非不同。在这个时间点，ACTH样肽补偿了因缺血而破坏的大鼠脑基因表达谱。因此，我们的结果可能有助于为未来的抗中风药物选择更有效的结构以及确定合适的中风后测试时间点。
