Natural melanocortins (MCs) have been used in the successful development of drugs with neuroprotective properties. Here, we studied the behavioral effects and molecular genetic mechanisms of two synthetic MC derivatives-ACTH(4–7)PGP (Semax) and ACTH(6–9)PGP under normal and acute restraint stress (ARS) conditions. Administration of Semax or ACTH(6–9)PGP (100 μg/kg) to rats 30 min before ARS attenuated ARS-induced behavioral alterations. Using high-throughput RNA sequencing (RNA-Seq), we identified 1359 differentially expressed genes (DEGs) in the hippocampus of vehicle-treated rats subjected to ARS, using a cutoff of >1.5 fold change and adjusted p-value (Padj) < 0.05, in samples collected 4.5 h after the ARS. Semax administration produced > 1500 DEGs, whereas ACTH(6–9)PGP administration led to <400 DEGs at 4.5 h after ARS. Nevertheless, ~250 overlapping DEGs were identified, and expression of these DEGs was changed unidirectionally by both peptides under ARS conditions. Modulation of the expression of genes associated with biogenesis, translation of RNA, DNA replication, and immune and nervous system function was produced by both peptides. Furthermore, both peptides upregulated the expression levels of many genes that displayed decreased expression after ARS, and vice versa, the MC peptides downregulated the expression levels of genes that were upregulated by ARS. Consequently, the antistress action of MC peptides may be associated with a correction of gene expression patterns that are disrupted during ARS.

Adverse effects in early ontogenesis can have a delayed influence on the functioning of various organs. We hypothesized that acute perinatal hypoxia would worsen the neurological status and functioning of cerebral arteries in adult rats. Two-day-old male Wistar rats underwent normobaric hypoxia for 2 h (8% O₂ content, «Hypoxia» group), while control rats from the same litters were placed in conditions with 21% O₂ content. «Hypoxia» rats exhibited delayed maturation of motor reflexes and reduced learning ability. The levels of key serum biochemical parameters did not differ between the two groups. Contractile responses induced by the thromboxane A₂ receptor agonist U46619 were increased in the basilar arteries of the «Hypoxia» group compared to «Control» rats. Endothelium-dependent relaxations to acetylcholine and arterial sensitivity to exogenous NO did not differ between the two groups. The NO-synthase inhibitor increased arterial contractility to a lesser extent in the «Hypoxia» group compared to the «Control» group, which was associated with decreased eNOS protein content in basilar arteries from «Hypoxia» rats. Thus, acute perinatal hypoxia impairs the neurological status of adult male rats, which may be partly associated with decreased blood supply to the brain as a result of weakened anticontractile influence of NO in basilar artery.