Ischemic brain stroke is one of the most serious and socially significant diseases. In addition to messenger RNAs (mRNAs), encoding protein, the study of regulatory RNAs in ischemic has exceptional importance for the development of new strategies for neuroprotection. Circular RNAs (circRNAs) have a closed structure, predominantly brain-specific expression, and remain highly promising targets of research. They can interact with microRNAs (miRNAs), diminish their activity and thereby inhibit miRNA-mediated repression of mRNA. Genome-wide RNA-Seq analysis of the subcortical structures of the rat brain containing an ischemic damage focus and penumbra area revealed 395 circRNAs changed their expression significantly at 24 h after transient middle cerebral artery occlusion model (tMCAO) conditions. Furthermore, functional annotation revealed their association with neuroactive signaling pathways. It was found that about a third of the differentially expressed circRNAs (DECs) originate from genes whose mRNA levels also changed at 24 h after tMCAO. The other DECs originate from genes encoding non-regulated mRNAs under tMCAO conditions. In addition, bioinformatic analysis predicted a circRNA–miRNA–mRNA network which was associated with the neurotransmission signaling regulation. Our results show that such circRNAs can persist as potential miRNA sponges for the protection of mRNAs of neurotransmitter genes. The results expanded our views about the neurotransmission regulation in the rat brain after ischemia–reperfusion with circRNA action.

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.

Complex diseases that affect the functioning of the central nervous system pose a major problem for modern society. Among these, ischemic stroke (IS) holds a special place as one of the most common causes of disability and mortality worldwide. Furthermore, Alzheimer’s disease (AD) ranks first among neurodegenerative diseases, drastically reducing brain activity and overall life quality and duration. Recent studies have shown that AD and IS share several common risk and pathogenic factors, such as an overlapping genomic architecture and molecular signature. In this review, we will summarize the genomics and RNA biology studies of IS and AD, discussing the interconnected nature of these pathologies. Additionally, we highlight specific genomic points and RNA molecules that can serve as potential tools in predicting the risks of diseases and developing effective therapies in the future.

Stroke remains the second leading cause of death worldwide. The development of new therapeutic agents focused on restoring vascular function and neuroprotection of viable tissues is required. In this study the neuroprotective activity of melanocortin-like ACTH(4–7)PGP and ACTH(6–9)PGP peptides was investigated in rat brain at 24 h after transient middle cerebral artery occlusion (tMCAO). The severity of ischemic damage, changes in the proliferative activity of neuroglial cells and vascularization of rat brain tissue were analyzed. The administration of peptides resulted in a significant increase in the volume density of neurons in the perifocal zone of infarction compared to rats subjected to ischemia and receiving saline. Immunohistochemical analysis of the proliferative activity of neuroglia cells using PCNA antibodies showed a significant increase in the number of proliferating cells in the penumbra and in the intact cerebral cortex of rats receiving peptide treatment. The effect of peptides on vascularization was examined using CD31 antibodies under tMCAO conditions, revealing a significant increase in the volume density of vessels and their sizes in the penumbra after administration of ACTH(4–7)PGP and ACTH(6–9)PGP. These findings confirm the neuroprotective effect of peptides due to the activation of neuroglia proliferation and the enhancement of collateral blood flow.

Circular RNAs (circRNAs) are non-coding RNAs that can significantly influence the regulation of gene expression in health and disease, including ischemic stroke. We identified 597 differentially expressed circRNAs (DECs) (fold change > 1.5; Padj < 0.05) in the striatum region encompassing the ischemic lesion and penumbra 24 h after ischemia–reperfusion injury (tMCAO) in rats, according to high-throughput RNA sequencing data (RNA-Seq). The DECs predominantly increased expression levels relative to those in sham-operated animals. In this study, we also compared these data with DECs we previously identified in the frontal cortex region containing the penumbra and healthy tissue. Furthermore, we bioinformatically constructed a network of competitive circRNA-microRNA-mRNA interactions characterizing the possible functions of DECs in brain areas with varying degrees of ischemic injury. We found that in both tissues, the identified DECs were involved in regulating the expression of genes associated with inflammation and neurotransmission. Moreover, in the striatum, most DECs decreased their expression, while in the frontal cortex, most DECs increased their expression. Thus, we demonstrated different circRNA activities in brain areas with varying degrees of injury. This result may indicate a role for these molecules in regulating brain cell responses, including those important for functional recovery after cerebral ischemia.