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

Abstract

Cerebral ischaemia is the most common cause of impaired brain function. Biologically active peptides represent potential drugs for reducing the damage that occurs after ischaemia. The synthetic melanocortin derivative, ACTH(4-7)PGP (Semax), has been used successfully in the treatment of patients with severe impairment of cerebral blood circulation. However, its molecular mechanisms of action within the brain are not yet fully understood. Previously, we used the transient middle cerebral artery occlusion (tMCAO) model to study the damaging effects of ischaemia–reperfusion on the brain transcriptome in rats. Here, using RNA-Seq analysis, we investigated the protective properties of the Semax peptide at the transcriptome level under tMCAO conditions. We have identified 394 differentially expressed genes (DEGs) (>1.5-fold change) in the brains of rats at 24 h after tMCAO treated with Semax relative to saline. Following tMCAO, we found that Semax suppressed the expression of genes related to inflammatory processes and activated the expression of genes related to neurotransmission. In contrast, ischaemia–reperfusion alone activated the expression of inflammation-related genes and suppressed the expression of neurotransmission-related genes. Therefore, the neuroprotective action of Semax may be associated with a compensation of mRNA expression patterns that are disrupted during ischaemia–reperfusion conditions.

Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

“…Mexidol and Semax have been studied as potential positive modulators of PGC-1α since, despite their different chemical natures, they exhibit similar patterns of neuroprotective effects, such as reduced brain damage, cognitive and sensorimotor deficits, and the ability to exert anti-exitotoxic, antioxidant, anti-inflammatory, and neurotrophic effects [ 45 , 47 , 48 , 49 , 50 , 55 , 56 , 57 , 58 , 81 ]. The multi-target neuroprotective activity of these drugs suggests that they have a common intracellular target molecule—the transcriptional coactivator PGC-1α, known for its pleiotropic potentiating effect on neuron viability and functionality.…”

“…The results of Filippenkov et al are consistent with our data on the anti-inflammatory effects of Semax. Using RNA-Seq analysis, the authors showed that Semax suppressed the inflammatory pathways and activated the brain’s neurotransmitter signaling pathways after focal ischemia [ 48 ]. Maintaining the anti-inflammatory (reparative) M2 phenotype of macrophages and microglia is crucial for PGC-1α induction in penumbral neurons since the M2 phenotype is the main source of neurotrophins, which are positive modulators of PGC-1α [ 17 , 90 ].…”

“…One of these drugs is the synthetic peptide Semax (a fragment of adrenocorticotrophin (ACTH) 4 – 7 conjugated with the C-terminal tripeptide Pro-Gly-Pro), which has been used as a nootropic and neuroprotective drug [ 43 , 44 ]. It has been shown that Semax decreases ischemic brain damage in clinical and animal studies by inducing the expression of neurotrophins and their receptors [ 45 , 46 , 47 , 48 , 49 , 50 ]. Semax contains a fragment of an amino acid sequence critical for the ACTH function but without hormonal activity [ 51 ].…”

Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4–7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia–Reperfusion

“…The study of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide acts on the brain transcriptome: it enhances the transcription of neurotrophins and their receptors [13,14], significantly affects the expression of genes associated with the processes of the immune response [15,16], suppresses the activation of the expression of genes involved in inflammation, and prevents the decrease in the expression of genes associated with neurotransmission [17].…”

Special Issue “Disentangling Mechanisms of Genomic Regulation of Cell Functions at the Gene Level”

“…A topic with a medical impact has been presented in the paper of Filipenko et al [4], who reported that the protective properties of a peptide drug (Semax) against ischemic stroke are associated with the compensation of mRNA expression patterns that are disrupted during ischaemic conditions. Leitao et al [5] reviewed the geographic distribution of genetic variants of the CYP2D6 gene which are associated with different metabolization profiles, with a focus on Amerindian populations.…”