Semax, an analog of ACTH(4−7), regulates expression of immune response genes during ischemic brain injury in rats

Abstract

Brain stroke continues to claim the lives of million people every year. To build the effective strategies for stroke treatment it is necessary to understand the neuroprotective mechanisms that are able to prevent the ischemic injury. Consisting of the ACTH fragment and the tripeptide Pro-Gly-Pro (PGP), the synthetic peptide Semax effectively protects brain against ischemic stroke. However, the molecular mechanisms underlying its neuroprotection and participation of PGP in them are still needed to be clarified. To reveal biological processes and signaling pathways, which are affected by Semax and PGP, we performed the transcriptome analysis of cerebral cortex of rats with focal cerebral ischemia treated by these peptides. The genome-wide biochip data analysis detected the differentially expressed genes (DEGs) and bioinformatic web-tool Ingenuity iReport found DEGs associations with several biological processes and signaling pathways. The immune response is the process most markedly affected by the peptide: Semax enhances antigen presentation signaling pathway, intensifies the effect of ischemia on the interferon signaling pathways and affects the processes for synthesizing immunoglobulins. Semax significantly increased expression of the gene encoding the immunoglobulin heavy chain, highly affects on cytokine, stress response and ribosomal protein-encoding genes after occlusion. PGP treatment of rats with ischemia attenuates the immune activity and suppresses neurotransmission in the CNS. We suppose that neuroprotective mechanism of Semax is realized via the neuroimmune crosstalk, and the new properties of PGP were found under ischemia. Our results provided the basis for further proteomic investigations in the field of searching Semax neuroprotection mechanism.

Novel Insights into the Protective Properties of ACTH(4-7)PGP (Semax) Peptide at the Transcriptome Level Following Cerebral Ischaemia–Reperfusion in Rats

“…There are many examples of the use of transcriptome analysis to study the mechanisms of action of a number of peptides including PACAP38 [ 54 ], Sal-like 4 peptide [ 55 ] and OxA [ 50 ]. The first genome-wide analysis of Semax action on the rat brain transcriptome was conducted using a permanent MCAO model that was induced by direct permanent electrical coagulation of the distal segment of the left middle cerebral artery [ 26 , 27 ]. The genome-wide biochip data analysis detected DEGs associated with several biological processes and signalling pathways.…”

“…Semax also stimulated the expression of genes that encode growth factors involved in trophic and protective processes, as well as the vascularization of damaged tissues. Additionally, Semax administration had a significant effect on the expression of genes associated with the immune response [ 26 , 27 ].…”

“…To rats of the IS group, the neuropeptide Semax was administered intraperitoneally at a dose of 10 μg/100 g rat weight as previously described [ 11 , 26 , 27 , 34 ] at 90 min, as well as at 2.5 and 6.5 h after tMCAO. To rats of the IR groups, saline was administered intraperitoneally at 90 min, as well as at 2.5 and 6.5 h after the surgical procedure.…”

“…Previously, using models of global incomplete cerebral ischaemia we have shown the effect of Semax on the expression of the limited number of genes that encode neurotrophic factors and their receptors [ 23 , 24 , 25 ]. Using microchips RatRef-12 BeadChips, it was shown that peptide Semax affects the expression of genes related to the immune and vascular systems in rat fronto-parietal cortex after permanent middle cerebral artery occlusion (pMCAO) [ 26 , 27 ]. At present, to study the molecular mechanisms of the effects of Semax, we used another model of transient middle cerebral artery occlusion (tMCAO).…”

The Role of Noncoding RNAs in Brain Cells during Rat Cerebral Ischemia

“…Genes unique to tMCAO were predominantly involved in the induction of inflammatory and oxidative stress, while pMCAO resulted in the expression of genes that were more associated with metabolic activity and cellular signaling [15]. A study of the dynamics of changes in gene expression in rat brain a day after pMCAO revealed a substantial number of genes that changed expression significantly and are involved in the development of ischemic damage, including those determining cell survival and death, the immune response, functioning of the vascular system, and also processes associated with hematopoiesis, immune cells, lymphocytes, leucocytes, and other cells [16].…”