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How does Semax enhance memory and protect the brain during injury?

“product By Nemo 17 days ago


Semax Stimulates Neurogenesis.

"Here, we found that a single application of Semax (50 μg/kg body weight) results in a maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosporylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively, in the rat hippocampus. Semax-treated animals showed a distinct increase in the number of conditioned avoidance reactions. We suggest that Semax affects cognitive brain functions by modulating the expression and the activation of the hippocampal BDNF/trkB system." (18)

Semax, an analog of ACTH(4–10) with cognitive effects, regulates ...

Semax, an analog of ACTH(4–10) with cognitive effects, regulates ...


Semax Improves Memory in Studies.

"On various models of amnesia (except that induced by the maximal electroshock) in mice, both mexidol and semax exhibited marked antiamnesic effects comparable with that of the reference nootrope drugs piracetam and oxyracetam. Mexidol showed a linear, while semax exhibited a bell-shaped reversible dose-effect relationships. Mexidol and semax inhibited the ortho- and antidromic population response spikes of CA1 pyramidal neurons of survival hippocampal slices in rats. It was estimated that mexidol (in contrast to semax) increased oxygen consumption in rat brain mitochondria and had a linear dose-effect relationship in a concentration range of 1-5 mM." (23)


Protective Effects of Semax on Cerebral Blood Vessels During Oxygen Deprivation.

"Intranasal administration of Semax for 6 days decreased the volume of cortical infarction and improved retention and performance of conditioned passive avoidance response." (10)

"Treatment with Semax reduces the levels of Vegfa mRNA in the frontal cortex (4, 8 and 12 h after occlusion) and the hippocampus (2 and 4 h after occlusion). The effect of PGP on the Vegfa gene expression was almost negligible. It was shown that Semax prevents the activating effect of hypoxia on the expression of the Vegfa gene at early stages of global cerebral ischemia. In turn, an increase in the level of Vegfa mRNA in the hippocampus 24 h after occlusion and Semax administration apparently reflects the neuroprotective properties of the drug." (1)

"The Vegf-b and Vegf-d genes were most affected by the peptides, which resulted in their most noticeable activation at 3 h after pMCAO. The level of Vegf-d transcripts decreased considerably, whereas the mRNA level of the Vegf-b gene was significantly increased after 72 h of treatment with each of the peptides. In addition, the effects of the peptides on the expression of the Vegf-b and Vegf-d genes were the opposite of the action of ischemia. It is suggested that the identified effects of the peptides diminish the effects of ischemia, thus participating in the positive therapeutic effect of Semax on ischemic stroke." (1)

"Another remarkable group of genes with Semax-induced alteration in expression levels consisted of genes involved in the vascular system. The expression of 24 and 12 genes was altered 3 and 24 hours after pMCAO, respectively." (2)

“As shown in Figure 3B, 24 h after occlusion, Semax affected the development of the endothelial tissue and the migration of smooth muscle cells, which was an indication of vessel formation and stabilization. Finally, another biological process, i.e., the activation of blood cells, was affected by Semax 24 h after pMCAO, which followed logically after the process of the formation of blood cells induced by Semax 3 h after the occlusion.” (2)

"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." (9)

"A clear correlation was observed between the NO content in the rat brain and the level of neurological disturbance manifestations in the ischemized animals. The synthetic peptide semax (a fragment of ACTH4-7 Pro-Gly-Pro) in a dose of 0.3 mg/kg prevented from the development of both neurological disturbances and excess NO production in the rat brain cortex." (19)

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The Effect of Semax on the Morphology and Proliferative Activity of Rat Brain Cells During Oxygen Deprivation.

" First, alleviation of the symptoms of vascular stasis during disturbances in brain blood circulation provides a histologically verifiable neuroprotective action. According to the available data (Cherkasova et al. 2001), the antithrombotic and anticoagulant action of Semax might play a significant role under conditions of ischemic damage. By preventing the aggregation and formation of erythrocyte debris in the microcirculatory channels, leading to reduced brain blood perfusion, Semax is likely to contribute to nervous tissue oxygenation and to hamper the development of secondary destructive reactions. Second, increased PCNA expression in the cell nuclei of ependymocytes, neuroglia, and blood vessel endothelium after Semax administration to animals of both control and experimental groups testifies to the stimulatory effect of this peptide on cells directly involved in the trophic supply of the CNS"


Semax Activates Many Cytokines and Gene Expressions of the Immune System.

“Semax-induced upregulation of transcripts was observed for a majority of the immune-response genes; among these, immunoglobulin genes formed the most prominent group, with half of them exhibiting the highest amplitude of expression alteration among the genes for which the level of transcripts was affected by the peptide." (16)

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“The neuroprotective and nootropic properties of Semax were previously associated only with events that are directly relevant to nervous tissues. Here, we uncovered the action of Semax on the immune system for the first time. Three hours after pMCAO, Semax acted on microglia and immune system cells. The process of leukocyte activation was affected most significantly (P-value = 7.6 × 10−8) in the immune response subgroup. The processes that developed 24 h after pMCAO, which involved leukocytes, remained significant. In addition, Semax affected DCs, the presence of which in rat cerebral hemisphere ischemia-damaged tissues had been reported by other researchers. DCs constitute a heterogeneous class of antigen-presenting cells that are capable of immune response initiation and cytokine production.

Both inflammation and immune response play an important role in ischemic stroke. It is well known that the penetration of inflammatory/immune cells into brain tissues during the postischemia hours aggravates the situation. In addition, no data have been reported to date indicating the presence of a specific cause-and-effect relationship between the penetration of leukocytes into the damaged tissues and the pathogenesis of the ischemia itself. However, some studies support the neuroprotective abilities of immune cells.

It should be mentioned that the most noticeable immune response to Semax action was observed at 24 h after pMCAO. A high level of immunoglobulin transcripts was found at that time point in the ischemized rat brain cortex. Several studies had shown previously that intravenous immunoglobulin (IVIG) has a strong neuroprotective effect against ischemic impairment of the brain.” (16)

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"Response of the vascular system to the administration of the neuropeptide Semax

Here, we found changes in the expression levels of several genes involved in the functioning of the vascular system as a response to Semax administration. The formation of new blood vessels in the ischemized areas represents one of the approaches used in the treatment of brain stroke. It should be mentioned that the presence of immune cells in the damaged tissues is a typical feature of post-ischemic revascularization. Three hours after pMCAO, Semax affected the expression of genes involved in vasculogenesis and the transcription levels of genes associated with hematopoiesis and the migration of endothelial cells. Some signal pathways are well known to be active in both hematopoiesis and vasculogenesis. Moreover, a large number of genes are expressed in both endothelial cells and hematopoietic precursor cells of the adult organism. Three hours after occlusion, Semax altered the expression of genes associated with the artery vasodilation process as well. Our earlier studies showed that capillary bore extension was observed as early as 15 min after the administration of the peptide... Our data showed that Semax is likely to influence processes that accompany the formation of new blood vessels during early ischemia cascade stages, as well as their stabilization at later stages." (15)

Finally, another biological process, i.e., the activation of blood cells, was affected by Semax 24 h after pMCAO, which followed logically after the process of the formation of blood cells induced by Semax 3 h after the occlusion." (15)


Semax Protects Neurons From Glutamate-induced Cell Death Despite Promoting Calcium Accumulation Inside Cells.

"Genes that regulate the levels of Ca2+ formed a separate group of genes exhibiting a significant Semax-induced alteration of expression 24 h after occlusion... The peptide increased the amount and mobility of immune cells and enhanced the expression of chemokine and immunoglobulin genes.” (16)

“Our results showed that Semax enhanced the expression of genes encoding protein products that promote intracellular Ca2+ accumulation. Possibly, the neuroprotective effect of Semax on ischemia-damaged nervous tissues includes an impact on processes involved in the incorporation of Ca2+ into cells.” (16)

"It is well known that ischemia-induced energy depletion in cells results in disturbed operation of potential-dependent calcium channels and Na+/Ca2+ pumps, excessive intracellular accumulation of Ca2+ ions, and neuronal death. However, it has been shown that Semax contributes to neuron survivability in the conditions of glutamate neurotoxicity that accompany ischemia. Some authors have suggested that cellular death is caused by the Ca2+ influx pathway, and not by Ca2+ load. Possibly, the neuroprotective effect of Semax on ischemia-damaged nervous tissues includes the impact of Ca2+ penetration into the cell on the regulatory processes. This idea is based on recent studies of the neuroprotective effect of Ca2+-activated potassium channels in conditions of brain ischemic damage."


Effects of Semax on Calcium Homeostasis of Neurons and Their Survival Under Conditions of Glutamate Toxicity.

"Semax (100 µM) and its Pro-Gly-Pro fragment (20 and 100 µM) delayed the development of calcium dysregulation and reduction of the mitochondrial potential in cultured cerebellar granule cells under conditions of glutamate neurotoxicity. Incubation with these peptides improved neuronal survival by on average 30%. The neuroprotective effect of semax in cerebral ischemia/hypoxia can be due to improvement of mitochondrial resistance to “calcium” stress." (8)


Semax, An ACTH(4-10) Analogue with Nootropic Properties, Activates Dopaminergic and Serotoninergic Brain Systems in Rodents.

"The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1–4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior D: -amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. (7)


Semax is a Potential Agent for ADHD and Rett syndrome

"Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis. In addition, Semax could improve selective attention and modulate brain development. Since ADHD is likely to be a neurodevelopmental disorder with disturbance in dopamine and BDNF function, it is proposed in this paper that Semax may have good therapeutic potential in ADHD. Furthermore, increased BDNF activity is found to improve Rett syndrome, a severe neurodevelopmental disorder which is, in the majority of cases, caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2)." (22)


Protective Effect of Peptide Semax on the Rat Heart Rate After Heart Damage.

“Semax did not affect cardiac work but partially prevented end-diastolic pressure growth in left ventricle as well as ameliorated cardiomyocyte hypertrophy and disproportionate growth of contractile and mitochondrial apparatus, thus exerting beneficial effect on the left ventricular remodeling and heart failure development late after myocardial infarction.” (3)


Protective Ability Against Metal Induced Cell Toxicity and High Affinity for Copper II ions.

"Noteworthy, a reduced copper induced cytotoxicity was observed in the presence of Semax by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on a SHSY5Y neuroblastoma and RBE4 endothelial cell lines." (4)


Semax Normalized the Circadian Locomotor Rhythm in Rats.

"The timing of locomotor activity is a major rhythmic output of the mammalian circadian system... exercise can also impact circadian rhythms across levels of organisation and in multiple tissues, including both the brain and periphery." (5)

"The chronic administration of nootropic drug Semax, a peptide analog of ACTH (4-10), normalized the circadian locomotor rhythm in rats (with an increase in its amplitude, a shift in the acrophase, and a change of the spectral characteristics) and reduced the integral chronobiological index. It is suggested that the rhythm-synchronizing chronotropic activity may be a part of the specific effect of this cognitive enhancer." (6)


Semax Boosts Endorphins by Inhibiting the Enkephalin-Degrading Enzymes.

"Dose-dependent effect of synthetic heptapeptides Semax (Met-Glu-His-Phe-Pro-Gly-Pro) and Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) on the enkephalin-degrading enzymes of human serum was demonstrated. The inhibitory effects of Semax (IC5010 μM) and Selank (IC5020 μM) are more pronounced than that of puromycin (IC5010 mM), bacitracin, and some other inhibitors of peptidases." (11)


Semax Inhibits Histamine Release from Mast Cell Activation

"We have shown that peptides Semax, Selank, PGPL FPG, GPG, PG and GP reduced the secretion of histamine from mast cells and increased the vascular permeability after the administration of Synacthen and LPS..." (12)

"Semax and prolyl-glycyl-proline in vitro prevented activation of mast cells with synacten and acetylcholine. The stabilizing effect of peptides on mast cells probably determines their antiulcer activity." (13)


Semax Stimulates Acetylcholine and Exploratory Activity

"Semax may approximately 1.5–1.7 fold increase survival of cholinergic basal forebrain neurons in vitro. Moreover, Semax (100 nM) stimulated activity of choline acetyltransferase in dissociated basal forebrain tissue cultures. However, the numbers of GABA-ergic neurons, total neuron specific enolase neurons were not affected." (14)

"At the age of four to eight weeks, Semax-treated rats displayed elevated exploratory activity, decreased anxiety level and improved passive avoidance conditioning. The results suggest that neonatal Semax administration modulates the development of the central nervous system." (17)


Semax in Glaucomatous Optic Neuropathy in Patients with Normalized Ophthalmic Tone.

"A complex of neuroprotective therapy, including a new Russian neuropeptide semax, was used in the treatment of glaucoma patients with normalized ophthalmic tone. Electrophysiological and computer methods of examination demonstrated the advantages of new therapy over traditional neuroprotective treatment for glaucoma. The efficiency is due to pathogenetic activity of semax possessing both neuroprotective and neurotrophic effects." (20)


Sourced Studies:

(1) Stavchanskii, V. V., et al. “Effect of Peptide Semax and Its C-Terminal Fragment PGP on Vegfa Gene Expression during Incomplete Global Cerebral Ischemia in Rats.” Molecular Biology, vol. 47, no. 3, May 2013, pp. 406–410, 10.1134/s0026893313030151.

(2) Expression of VEGF Family Genes and Their Receptors in Experimental Focal Ischemia of the Rat Brain.” Journal of Molecular Neuroscience: MN, vol. 49, no. 2, 1 Feb. 2013, pp. 328–333, www.ncbi.nlm.nih.gov/pubmed/22772900, 10.1007/s12031-012-9853-y.

(3) Gavrilova, S. A., et al. “[Protective Effect of Peptide Semax (ACTH(4-7)Pro-Gly-Pro) on the Rat Heart Rate after Myocardial Infarction].” Rossiiskii Fiziologicheskii Zhurnal Imeni I.M. Sechenova, vol. 92, no. 11, 1 Nov. 2006, pp. 1305–1321, www.ncbi.nlm.nih.gov/pubmed/17385423.

(4) Tabbì, Giovanni, et al. “Semax, an ACTH4-10 Peptide Analog with High Affinity for Copper(II) Ion and Protective Ability against Metal Induced Cell Toxicity.” Journal of Inorganic Biochemistry, vol. 142, 1 Jan. 2015, pp. 39–46, www.sciencedirect.com/science/article/pii/S0162013414002505, 10.1016/j.jinorgbio.2014.09.008.

(5) Hughes, Alun Thomas Lloyd. “Locomotor Exercise and Circadian Rhythms in Mammals.” Current Opinion in Physiology, vol. 5, 1 Oct. 2018, pp. 51–57, www.sciencedirect.com/science/article/pii/S2468867318300919, 10.1016/j.cophys.2018.07.001.

(6) Arushanian, E. B., and A. V. Popov. “[Chronotropic Activity of Semax].” Eksperimental’naia I Klinicheskaia Farmakologiia, vol. 71, no. 2, 1 Mar. 2008, pp. 14–16, www.ncbi.nlm.nih.gov/pubmed/18488900.

(7) Eremin, Kirill O., et al. “Semax, An ACTH(4-10) Analogue with Nootropic Properties, Activates Dopaminergic and Serotoninergic Brain Systems in Rodents.” Neurochemical Research, vol. 30, no. 12, Dec. 2005, pp. 1493–1500, 10.1007/s11064-005-8826-8.

(8) Storozhevykh, T. P., et al. “Effects of Semax and Its Pro-Gly-Pro Fragment on Calcium Homeostasis of Neurons and Their Survival under Conditions of Glutamate Toxicity.” Bulletin of Experimental Biology and Medicine, vol. 143, no. 5, May 2007, pp. 601–604, 10.1007/s10517-007-0192-x

(9) Stavchansky, Vasily V., et al. “The Effect of Semax and Its C-End Peptide PGP on the Morphology and Proliferative Activity of Rat Brain Cells During Experimental Ischemia: A Pilot Study.” Journal of Molecular Neuroscience, vol. 45, no. 2, 9 July 2010, pp. 177–185, 10.1007/s12031-010-9421-2.

(10) Romanova, G. A., et al. “Neuroprotective and Antiamnesic Effects of Semax during Experimental Ischemic Infarction of the Cerebral Cortex.” Bulletin of Experimental Biology and Medicine, vol. 142, no. 6, Dec. 2006, pp. 663–666, 10.1007/s10517-006-0445-0.

(11) Kost, N. V., et al. “[Semax and Selank Inhibit the Enkephalin-Degrading Enzymes from Human Serum]].” Russian Journal of Bioorganic Chemistry, vol. 27, no. 3, 2001, pp. 156–159, 10.1023/a:1011373002885.

(12) “The Connection Between Structure Modification and Anti-Inflammatory Effects of Prolyl-Glycyl-Proline (PGP) - ProQuest.” Search.Proquest.Com, search.proquest.com/openview/a19dba16907cd5fa6ffc0383f325c70c/1?pq-origsite=gscholar&cbl=54427.

(13) Umarova, B. A., et al. “Secretory Activity of Mast Cell during Stress: Effect of Prolyl-Glycyl-Proline and Semax.” Bulletin of Experimental Biology and Medicine, vol. 136, no. 4, Oct. 2003, pp. 325–327, 10.1023/b:bebm.0000010942.14275.50.

(14) Grivennikov, Igor A., et al. “Effects of Behaviorally Active ACTH (4–10) Analogue – Semax on Rat Basal Forebrain Cholinergic Neurons.” Restorative Neurology and Neuroscience, vol. 26, no. 1, 1 Jan. 2008, pp. 35–43, content.iospress.com/articles/restorative-neurology-and-neuroscience/rnn00419.

(15) Medvedeva, Ekaterina V, et al. “The Peptide Semax Affects the Expression of Genes Related to the Immune and Vascular Systems in Rat Brain Focal Ischemia: Genome-Wide Transcriptional Analysis.” BMC Genomics, vol. 15, no. 1, 2014, p. 228, 10.1186/1471-2164-15-228.

(16) Medvedeva, Ekaterina V, et al. “The Peptide Semax Affects the Expression of Genes Related to the Immune and Vascular Systems in Rat Brain Focal Ischemia: Genome-Wide Transcriptional Analysis.” BMC Genomics, vol. 15, no. 1, 2014, p. 228, 10.1186/1471-2164-15-228.

(17) Sebentsova, E. A., et al. “[Long-Lasting Behavioral Effects of Chronic Neonatal Treatment with ACTH (4-10) Analogue Semax in White Rat Pups].” Zhurnal Vysshei Nervnoi Deiatelnosti Imeni I P Pavlova, vol. 55, no. 2, 1 Mar. 2005, pp. 213–220, www.ncbi.nlm.nih.gov/pubmed/15895862.

(18) Dolotov, Oleg V., et al. “Semax, an Analog of ACTH(4–10) with Cognitive Effects, Regulates BDNF and TrkB Expression in the Rat Hippocampus.” Brain Research, vol. 1117, no. 1, 30 Oct. 2006, pp. 54–60, www.sciencedirect.com/science/article/abs/pii/S0006899306022955, 10.1016/j.brainres.2006.07.108.

(19) Fadiukova, O. E., et al. “[Semax Prevents Elevation of Nitric Oxide Generation Caused by Incomplete Global Ischemia in the Rat Brain].” Eksperimental’naia I Klinicheskaia Farmakologiia, vol. 64, no. 2, 1 Mar. 2001, pp. 31–34, www.ncbi.nlm.nih.gov/pubmed/11548444.

(20) Kurysheva, N. I., et al. “[Semax in the Treatment of Glaucomatous Optic Neuropathy in Patients with Normalized Ophthalmic Tone].” Vestnik Oftalmologii, vol. 117, no. 4, 1 July 2001, pp. 5–8, www.ncbi.nlm.nih.gov/pubmed/11569188.

(21) Stavchansky, Vasily V., et al. “The Effect of Semax and Its C-End Peptide PGP on the Morphology and Proliferative Activity of Rat Brain Cells During Experimental Ischemia: A Pilot Study.” Journal of Molecular Neuroscience, vol. 45, no. 2, 9 July 2010, pp. 177–185, 10.1007/s12031-010-9421-2.

(22) Tsai, Shih-Jen. “Semax, an Analogue of Adrenocorticotropin (4–10), Is a Potential Agent for the Treatment of Attention-Deficit Hyperactivity Disorder and Rett Syndrome.” Medical Hypotheses, vol. 68, no. 5, 1 Jan. 2007, pp. 1144–1146, www.sciencedirect.com/science/article/abs/pii/S0306987706005391, 10.1016/j.mehy.2006.07.017.

(23) Iasnetsov, Vik V., and T. A. Voronina. “[Antihypoxic and Antiamnesic Effects of Mexidol and Semax].” Eksperimental’naia I Klinicheskaia Farmakologiia, vol. 73, no. 4, 1 Apr. 2010, pp. 2–7, www.ncbi.nlm.nih.gov/pubmed/20486550.


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