Changes of transcriptomic activity in rat brain cells under the influence of synthetic adrenocorticotropic hormone-like peptides

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Abstract

Synthetic peptides have a wide range of clinical effects. Of particular interest are peptides based on adrenocorticotropic hormone (ACTH) both as already used and as potential drugs for preventing the consequences of cerebral ischemia. However, it is necessary to study the peptide influence on brain cells under normal physiological conditions, including understanding the risks of their use. Here, we used high-throughput RNA sequencing (RNA-Seq) to identify differentially expressed genes (DEGs) in the frontal cortex of rats receiving intraperitoneal administration of ACTH-like peptides ACTH(4-7)PGP (Semax) and ACTH(6–9)PGP or saline. We identified 258 and 228 DEGs, respectively, with a threshold of > 1.5 and Padj < 0.05 at 22.5 hours after the first administration of Semax and ACTH(6-9)PGP. Metabolic pathways, characterizing both the general and specific effects of peptides on the transcriptome were identified. Both peptides predominantly caused a decrease in the expression of genes associated with the immune system. At the same time, when comparing the effects of ACTH(6-9)PGP relative to Semax, DEGs were identified that characterized the main differences in the effects of the peptides. These genes were mostly downregulated and associated with neurosignaling systems and regulation of ion channels and characterized differences in the effects of peptides. Our data show how differences in the structure of ACTH derivatives are associated with changes in the brain cell transcriptome following exposure to these related peptides. Furthermore, our results evident that when studying the influence of regulatory peptides on the transcriptome in pathological conditions, it is necessary to take into account their actions under normal physiological conditions.

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About the authors

I. B. Filippenkov

National Research Centre “Kurchatov Institute”

Author for correspondence.
Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

N. Y. Glazova

National Research Centre “Kurchatov Institute”; Lomonosov Moscow State University

Email: filippenkov-ib.img@yandex.ru

Faculty of Biology

Russian Federation, 123182 Moscow; 119991 Moscow

E. A. Sebentsova

National Research Centre “Kurchatov Institute”; Lomonosov Moscow State University

Email: filippenkov-ib.img@yandex.ru

Faculty of Biology

Russian Federation, 123182 Moscow; 119991 Moscow

V. V. Stavchansky

National Research Centre “Kurchatov Institute”

Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

L. A. Andreeva

National Research Centre “Kurchatov Institute”

Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

N. F. Myasoedov

National Research Centre “Kurchatov Institute”

Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

N. G. Levitskaya

National Research Centre “Kurchatov Institute”; Lomonosov Moscow State University

Email: filippenkov-ib.img@yandex.ru

Faculty of Biology

Russian Federation, 123182 Moscow; 119991 Moscow

S. A. Limborska

National Research Centre “Kurchatov Institute”

Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

L. V. Dergunova

National Research Centre “Kurchatov Institute”

Email: filippenkov-ib.img@yandex.ru
Russian Federation, 123182 Moscow

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2. Fig. 1. The structure of peptides ACTH(4-7)PGP (semax) and ACTH(6-9)PGP (a). Schematic representation of a section of the rat brain with shading indicating the localization of the area of the frontal cortex taken for RNA sequencing (b). Study scheme (c)

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3. 2. RNA-Seq analysis of the effect of semax and ACTH(6-9)PGP on the transcriptome of the rat frontal cortex. The volcano-plot graphs illustrate the differences in mRNA expression between the norm + semax (NS) and norm + saline (NV) groups (a), as well as norm + ACTH(6-9)PGP (NA) and norm + saline (NV) (b). 10 DEGS were presented, which showed the largest multiple change in expression in the comparisons NS vs. NV (b) and NA vs. NV (d). Each comparison group included 3 animals. The data is presented as the average ± standard error of the average

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4. 3. Comparison of the results of RNA-Seq in experiments with the introduction of semax and ACTH(6-9)PGP. Venn diagrams (a–b) illustrate the results obtained for two pairwise comparisons "norm + semax" (NS) vs. "norm + saline solution" (NV) and "norm + ACTH(6-9)PGP" (NA) vs. "norm + saline solution" (NV): for all DEG (a), only for those with increased expression (b) and only for those with decreased expression (c). The numbers at the intersection of different sets of genes in the Venn diagram indicate the number of DEG (multiplicity > 1.5; Padj < 0.05) according to RNA-Seq data. The relative expression values for 10 genes from each segment are shown in the Venn diagram (panel a): genes with the largest multiple expression variation in NS vs. NV and lie within the intersection of the sets of DEG (d); DEG with the largest multiple expression change in NS vs. NV, but not DEG in NA vs. NV (e); DEG with the largest multiple expression change in NA vs. NV, but not DEG in NS vs. NV (e). The data is presented as the mean ± the standard error of the mean

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5. Fig. 4. Comparison of the results of RNA-Seq in experiments with ACTH(6-9)PGP administration relative to the action of semax. The "volcano-plot" graph illustrates the differences in mRNA expression between the "norm + ACTH(6-9)PGP" (NA) and "norm + semax" (NS) (a) groups. 10 genes are presented that showed the greatest multiple change in expression compared to NA vs. NS (multiplicity > 1.5; Padj < 0.05) according to RNA-Seq data (b)

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6. Fig. 5. Signaling pathways associated with the effect of semax and ACTH(6-9)PGP on the transcriptome of a region of the frontal cortex of rats. The analysis was performed using the DAVID v2021 program. Schematic comparison of annotations (paths) related to DEG obtained in three paired comparisons NS vs. NV, NA vs. NV and NA vs. NS in the form of a Venn diagram (a). The number of annotations is indicated by numbers in the diagram segments. The signal pathways lying in the segments on the Venn diagram are shown: common for NS vs comparisons. NV and NA vs. NV (b), as well as comparisons specific to NS vs. NV (c), NA vs. NV (d), and NA vs. NS (e). Panels (b), (c), and (e) show all paths lying in the corresponding segment on the Venn diagram, and panel (d) shows only 5 of the 22 paths with the minimum Padj value (the p value adjusted using the Benjamini–Hochberg procedure) in NA vs. NV. Padj values are presented for each pathway, as well as the number of increased and decreased gene expression in the corresponding pairwise comparison. Only DEG and pathways with Padj < 0.05 were selected for analysis. Each comparison group included 3 animals. Inflammatory bowel disease – inflammatory bowel disease; NOD-like receptor signaling pathway – NOD-like receptor signaling pathway; Tuberculosis – tuberculosis; Coronavirus disease – COVID-19 (coronavirus disease); Influenza A – influenza A; Systemic lupus erythematosus – systemic lupus erythematosus; Antigen processing and presentation – antigen processing and presentation; Phagosome – phagosome; Pertussis – whooping cough; Leishmaniasis – leishmaniasis; Complement and coagulation cascades – cascades of complement and coagulation; Epstein-Barr virus infection – Epstein–Barr virus infection; Immune System – immune system; Staphylococcus aureus infection – staphylococcus aureus infection; Innate Immune System – innate immune system); Th17 cell differentiation – differentiation of T helper cells 17; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell - immunoregulatory interactions between lymphoid and non–lymphoid cells; Neutrophil degradation – degranulation neutrophils; Viral myocarditis – viral myocarditis; Herpes simplex virus 1 infection – infection of the herpes simplex virus 1; Natural killer cell mediated cytotoxicity – cytotoxicity mediated by natural killer cells; Neuronal System – neural system

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7. 6. Networks reflecting the general and specific effects of semax and ACTH(6-9)PGP on the transcriptome of the rat frontal cortex. Only the genes that changed expression under the action of both semax and ACTH(6-9)PGP (NS vs. NV and NA vs. NV) (a); only under the action of semax (NS vs. NV), but not ACTH(6-9)PGP (NA vs. NV) (b); only under the action of ACTH(6-9)PGP (NA vs. NV), but not semax (NS vs. NV) (b); under the action of ACTH(6-9)PGP relative to semax (NA vs. NS) (d). These groups of genes (a–g) are involved in the presentation of KP1–KP4, respectively. In the diagrams, the genes are presented in rectangular blocks colored according to the differential expression of the genes in the comparison groups – NS vs. NV (a and b), NA vs. NV (c), NA vs. NS (d). The paths are indicated by white ovals. The lines connecting genes and pathways indicate the involvement of the protein products of the genes in the functioning of the pathway. The DAVID v2021 program was used to annotate DEG functions in terms of paths from the KEGG and REACTOME databases. The network was built using Cytoscape 3.9.2

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8. Suppl. 1.
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9. Suppl. 2.
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