Filippenkov Ivan B, Shpetko Yana Yu, Ales Daria A, Stavchansky Vasily V, Denisova Alina E, Yuzhakov Vadim V, Fomina Natalia K, 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, Moscow 123182, Russia.
Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, Ostrovitianov Str. 1, Moscow 117997, Russia.
Int J Mol Sci. 2025 Jun 28;26(13):6256. doi: 10.3390/ijms26136256.
In the treatment of ischemic stroke, an innovative approach is the use of neuroprotective compounds. Natural peptides, including adrenocorticotropic hormone (ACTH), can serve as the basis for such drugs. Previously, a significant effect of non-hormonal ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP peptides on the functions of the nervous system was shown. Also, while using RNA-Seq, we firstly revealed differentially expressed genes (DEGs) that associated with peptides in the penumbra-associated region of the frontal cortex (FC) of rats at 24 h after transient middle cerebral artery occlusion (tMCAO) model. Peptides significantly reduced profile disturbances caused by ischemia for almost two-thousand DEGs in FC related to the neurotransmitter and inflammatory response. Here, we studied how peptides affected the expression of genes in the striatum with an ischemic focus, predominantly. The same animals from which we previously acquired FC were used to collect striatum samples. Peptides generated fewer DEGs in the striatum than in the FC. Both peptides tended to normalize the profile of disturbances caused by ischemia for hundreds of DEGs, whereas 152 genes showed an even more affected profile in the striatum under ACTH(6-9)PGP action. These DEGs were associated with inflammation, predominantly. About hundred genes were overlapped between both peptides in both tissues and were associated with neuroactive ligand-receptor interaction, predominantly. Thus, genes that are associated with the ACTH-like peptide action in rat brain regions with varying levels of ischemia injury were identified. Moreover, differential spatial regulation of the ischemia process in the rat brain at the transcriptome levels was discovered under peptides with different ACTH structures. We suppose that our results may be useful for selecting more effective neuroprotective drug structures in accordance with their specific tissue/damage therapeutic impact.
在缺血性中风的治疗中，一种创新方法是使用神经保护化合物。包括促肾上腺皮质激素（ACTH）在内的天然肽可作为此类药物的基础。此前，已显示非激素ACTH(4-7)PGP（Semax）和ACTH(6-9)PGP肽对神经系统功能有显著影响。此外，在使用RNA测序时，我们首次揭示了在短暂性大脑中动脉闭塞（tMCAO）模型后24小时，大鼠额叶皮质（FC）半暗带相关区域中与肽相关的差异表达基因（DEG）。肽显著减少了FC中近两千个与神经递质和炎症反应相关的DEG因缺血引起的谱紊乱。在此，我们主要研究了肽如何影响有缺血灶的纹状体中的基因表达。使用了之前获取FC的同一批动物来收集纹状体样本。肽在纹状体中产生的DEG比在FC中少。两种肽都倾向于使数百个DEG因缺血引起的紊乱谱正常化，而在ACTH(6-9)PGP作用下，纹状体中有152个基因的谱受到的影响更大。这些DEG主要与炎症相关。两种组织中两种肽之间约有一百个基因重叠，且主要与神经活性配体-受体相互作用相关。因此，确定了在大鼠脑区中与不同缺血损伤水平下ACTH样肽作用相关的基因。此外，发现在具有不同ACTH结构的肽作用下，大鼠脑缺血过程在转录组水平上存在差异空间调节。我们认为，我们的结果可能有助于根据其特定的组织/损伤治疗影响来选择更有效的神经保护药物结构。
