acth-(4-7)--pro-gly-pro- and Brain-Ischemia

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

Topics: Adrenocorticotropic Hormone; Animals; Behavior, Animal; Brain Ischemia; Disease Models, Animal; DNA Replication; Gene Expression; Gene Expression Profiling; Hippocampus; Immune System; Male; Melanocortins; Peptide Fragments; Peptides; Rats; Rats, Wistar; Restraint, Physical; RNA-Seq; Stress, Physiological; Transcriptome

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.

Topics: Adrenocorticotropic Hormone; Animals; Brain; Brain Ischemia; Disease Models, Animal; Male; Neuroprotective Agents; Peptide Fragments; Proteome; Rats; Rats, Wistar; Reperfusion Injury; RNA-Seq; Transcriptome

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

Topics: Adrenocorticotropic Hormone; Animals; Brain; Brain Ischemia; Disease Models, Animal; Humans; Infarction, Middle Cerebral Artery; Peptide Fragments; Rats; Reperfusion Injury; RNA-Seq; Transcriptome

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

Topics: Adrenocorticotropic Hormone; Animals; Antigen Presentation; Brain Ischemia; Disease Models, Animal; Gene Expression Profiling; Genes, Immunoglobulin Heavy Chain; Immunoglobulin Heavy Chains; Male; Middle Cerebral Artery; Neuroprotective Agents; Oligopeptides; Peptide Fragments; Proline; Rats; Rats, Wistar; Stress, Physiological; Transcriptome

A new mixture of tripeptides (NMT: H-Lys-Asp-Glu-OH, H-Asp-Glu-Pro-OH, H-Asp-Glu-Arg-OH) in doses of 150 and 300 mg/kg per day produces clearly pronounced neuroprotective effect in rats with brain ischemia and decreases neurologic deficiency 1.1 times more effectively than reference drug semax. NMT (10, 50 and 150 mg/kg) had marked antihypoxic effect on mice in hermetic and altitude chamber. NMT in doses of 10 and 50 mg/kg was more effective than semax in hermetic chamber (1.3 and 1.5 times, respectively) and in a dose of 150 mg/kg in altitude chamber (1.9 times). NMT (50 and 150 mg/kg) had also marked antiamnesic effect on model amnesia caused by scopolamine in rats and was more effective (1.5 and 1.4 times, respectively) than semax in equal doses. NMT (50 and 150 mg/kg) also had marked antiamnesic effect on model amnesia caused by maximal electroshock and complex extreme factors in mice and in both doses was 4 times more effective than semax on the first model and in a dose of 150 mg/kg was 2.9 times more effective on the second model. NMT (50 mg/kg) increased the amplitude of transcallosal evoked potential in rat brain by 69% and was more effective than semax in equal dose. Thus, NMT is a promising neurotropic drug with neuroprotective, antihypoxic and antiamnesic activity.

Topics: Adrenocorticotropic Hormone; Amnesia; Animals; Brain Ischemia; Electroshock; Evoked Potentials, Motor; Hypoxia; Male; Mice; Neuroprotective Agents; Nootropic Agents; Oligopeptides; Peptide Fragments; Rats; Scopolamine

The nootropic neuroprotective peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has proved efficient in the therapy of brain stroke; however, the molecular mechanisms underlying its action remain obscure. Our genome-wide study was designed to investigate the response of the transcriptome of ischemized rat brain cortex tissues to the action of Semax in vivo.. The gene-expression alteration caused by the action of the peptide Semax was compared with the gene expression of the "ischemia" group animals at 3 and 24 h after permanent middle cerebral artery occlusion (pMCAO). The peptide predominantly enhanced the expression of genes related to the immune system. Three hours after pMCAO, Semax influenced the expression of some genes that affect the activity of immune cells, and, 24 h after pMCAO, the action of Semax on the immune response increased considerably. The genes implicated in this response represented over 50% of the total number of genes that exhibited Semax-induced altered expression. Among the immune-response genes, the expression of which was modulated by Semax, genes that encode immunoglobulins and chemokines formed the most notable groups. In response to Semax administration, 24 genes related to the vascular system exhibited altered expression 3 h after pMCAO, whereas 12 genes were changed 24 h after pMCAO. These genes are associated with such processes as the development and migration of endothelial tissue, the migration of smooth muscle cells, hematopoiesis, and vasculogenesis.. Semax affects several biological processes involved in the function of various systems. The immune response is the process most markedly affected by the drug. Semax altered the expression of genes that modulate the amount and mobility of immune cells and enhanced the expression of genes that encode chemokines and immunoglobulins. In conditions of rat brain focal ischemia, Semax influenced the expression of genes that promote the formation and functioning of the vascular system.The immunomodulating effect of the peptide discovered in our research and its impact on the vascular system during ischemia are likely to be the key mechanisms underlying the neuroprotective effects of the peptide.

Topics: Adrenocorticotropic Hormone; Animals; Brain Ischemia; Cerebral Cortex; Endothelium, Vascular; Gene Expression Regulation; Genome; Immune System; Male; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Wistar; Transcriptome

The neuropeptide preparation Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has been employed successfully in clinical practice for treating patients with severe brain blood circulation disorders. In spite of numerous studies, many aspects of the therapeutic effects of this preparation remain unknown. In this context, the effects of Semax and its C-end tripeptide PGP on the functional morphology of nervous tissue cells were studied in the normal rat brain and in a model of incomplete global rat brain ischemia. In control animals, both peptides activated the capillary network and caused similar morphological changes to neurons and the neuropil regions. We show here for the first time at the histological level that Semax and PGP increased proliferation of the neuroglia, blood vessel endothelium, and progenitor cells in the subventricular zone. In these experimental conditions, only Semax abated the manifestation of ischemic damage to the nervous tissue. This was probably attributable to a decrease in vascular stasis symptoms as well as the trophic effect of the peptide.

Topics: Adrenocorticotropic Hormone; Animals; Brain; Brain Ischemia; Cell Proliferation; Humans; Male; Neuroprotective Agents; Oligopeptides; Peptide Fragments; Pilot Projects; Proline; Rats; Rats, Wistar

Consisting of a fragment of ACTH(4-7) and C-terminal PGP tripeptide, the polypeptide Semax is successfully used for acute stroke therapy. Previous experiments showed rapid induction of Bdnf, Ngf, and TrkB expression in intact rat hippocampus following Semax treatment. To investigate the mRNA expression of neurotrophins and their receptors after treatment with either Semax or PGP, the rat brains were analyzed at three time points following a permanent middle cerebral artery occlusion (pMCAO). We have shown for the first time that both Semax and PGP activate the transcription of neurotrophins and their receptors in the cortex of rats subjected to pMCAO. The profiles of transcription alteration under PGP and Semax treatment were partially overlapped. Semax enhanced the transcription of Bdnf, TrkC, and TrkA 3 h after occlusion, Nt-3 and Ngf 24 h after occlusion, and Ngf 72 h after occlusion. PGP enhanced the transcription of Bdnf and TrkC 3 h after pMCAO and Ngf, TrkB, TrkC, and TrkA 24 h after pMCAO. The analysis of the transcription alterations under PGP and Semax treatment in the cortex of rats without surgery, sham-operated rats and rats subjected to pMCAO revealed that Semax selectively affected the transcription of neurotrophins and their receptors in the ischemic rat cortex, whereas the influence of PGP was mainly unspecific.

Topics: Adrenocorticotropic Hormone; Animals; Brain Ischemia; Cerebral Cortex; Gene Expression Regulation; Male; Nerve Growth Factors; Oligopeptides; Peptide Fragments; Rats; Rats, Wistar; Receptors, Nerve Growth Factor; RNA, Messenger; Transcription, Genetic

This work investigates whether nitric oxide production and lipid peroxidation contribute to the pathophysiology of ischemia and whether glycine and a novel Russian compound, Semax are neuroprotective via a mechanism involving the regulation nitric oxide (NO) and lipid peroxidation. In brief, nitric oxide and indices of lipid peroxidation were elevated following global ischemia. While glycine proved ineffective in reducing NO levels or ameliorating the neurological deficits following global ischemia, Semax proved to be highly effective in abating the rise in nitric oxide and restoring neurologic functioning.

Topics: Adrenocorticotropic Hormone; Animals; Brain Ischemia; Cerebral Cortex; Glycine; Lipid Peroxidation; Male; Nitric Oxide; Nootropic Agents; Peptide Fragments; Rats; Rats, Wistar

Semax is the first domestic nootropic drug of an unexhausted type from the group of neuropeptides. In experimental studies it showed angioprotective, antihypoxic and neurotrophic activity in the doses 100-150 micrograms/kg. A combined clinical-electrophysiologic study revealed its high efficiency in acute ischemic stroke. A clinical trial was performed of immunobiochemical mechanisms of neuroprotective properties of Semax in acute period of ischemic stroke. A retrospective comparative clinicoimmunobiochemical analysis provided objective data on the molecular level on activating influence of Semax on antiinflammatory postischemic reactions in the brain. Shifting neuromediatory balance toward a prevalence of the antiinflammatory agents (interleukin-10, tumor necrosis factor-alpha) over the factors maintaining the inflammation (interleukin-8, C-reactive protein).

Topics: Acute Disease; Adrenocorticotropic Hormone; Brain; Brain Ischemia; C-Reactive Protein; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-10; Neuroprotective Agents; Peptide Fragments; Retrospective Studies; Time Factors; Tumor Necrosis Factor-alpha

Topics: Adrenocorticotropic Hormone; Animals; Arterial Occlusive Diseases; Brain Ischemia; Carotid Artery Diseases; Male; Neuroprotective Agents; Peptide Fragments; Rats

Topics: Adrenocorticotropic Hormone; Animals; Brain Ischemia; Cerebrovascular Circulation; Injections, Intraperitoneal; Male; Peptide Fragments; Rats