Insight into Glyproline Peptides’ Activity through the Modulation of the Inflammatory and Neurosignaling Genetic Response Following Cerebral Ischemia–Reperfusion

Abstract

Glyprolines are Gly-Pro (GP)- or Pro-Gly (PG)-containing biogenic peptides. These peptides can act as neutrophil chemoattractants, or atheroprotective, anticoagulant, and neuroprotective agents. The Pro-Gly-Pro (PGP) tripeptide is an active factor of resistance to the biodegradation of peptide drugs. The synthetic Semax peptide, which includes Met-Glu-His-Phe (MEHF) fragments of adrenocorticotropic hormone and the C-terminal tripeptide PGP, serves as a neuroprotective drug for the treatment of ischemic stroke. Previously, we revealed that Semax mostly prevented the disruption of the gene expression pattern 24 h after a transient middle cerebral artery occlusion (tMCAO) in a rat brain model. The genes of this pattern were grouped into an inflammatory cluster (IC) and a neurotransmitter cluster (NC). Here, using real-time RT-PCR, the effect of other PGP-containing peptides, PGP and Pro-Gly-Pro-Leu (PGPL), on the expression of a number of genes in the IC and NC was studied 24 h after tMCAO. Both the PGP and PGPL peptides showed Semax-unlike effects, predominantly without changing gene expression 24 h after tMCAO. Moreover, there were IC genes (iL1b, iL6, and Socs3) for PGP, as well as IC (iL6, Ccl3, Socs3, and Fos) and NC genes (Cplx2, Neurod6, and Ptk2b) for PGPL, that significantly changed in expression levels after peptide administration compared to Semax treatment under tMCAO conditions. Furthermore, gene enrichment analysis was carried out, and a regulatory gene network was constructed. Thus, the spectra of the common and unique effects of the PGP, PGPL, and Semax peptides under ischemia–reperfusion were distinguished.

Synthetic Adrenocorticotropic Peptides Modulate the Expression Pattern of Immune Genes in Rat Brain following the Early Post-Stroke Period

“…Nonetheless, this effect might not relate to the influence of PGP only. We have previously shown that the effect of PGP injections on the expression of inflammatory cluster genes was unlike the Semax effect 24 h after tMCAO [25]. Thus, the inflammatory-related genes were DEGs after Semax but non-DEGs after PGP administration under IR conditions.…”

“…Moreover, Semax was associated with a correction to the gene expression patterns that are disrupted during cerebral ischemia 24 h after tMCAO. The genes in this pattern were grouped into an inflammatory cluster and a neurotransmitter cluster [24,25]. A number of Semax effects have also been demonstrated at the level of protein expression in the ischemic brain of rats [26].…”

Neuroprotective Peptides and New Strategies for Ischemic Stroke Drug Discoveries

“…Using real-time RT-PCR, we studied the effects of PGP and another PGP-containing the Pro-Gly-Pro-Leu (PGPL) peptide on the expression of a number of inflammatory cluster (IC) and neurotransmitter cluster (NC) genes in rat brain under transient MCAO. Then, we compared the studied peptide effects with the action of Semax under IR conditions [96,117]. Both PGP and PGPL peptides showed an effect dissimilar to the effects of Semax at 24 h after transient MCAO.…”

“…The expression levels of these genes changed significantly after the corresponding peptide, compared to Semax administration. Based on the results of the analysis of gene expression under experimental conditions using bioinformatic approaches, a functional network was built that illustrates the spectra of common and unique effects of PGP, PGPL, and Semax peptides [117]. Thus, transcriptomic analysis, in addition to studying the molecular mechanisms of action of peptides, makes it possible to reveal the relationship between their chemical structure and possible effects at the genomic and functional levels.…”