Semax Stimulates Neurogenesis.
Scientists observed Semax a at dosage of 50 ug/kg body weight of rats to upregulate BDNF protein by 1.4 fold along with 1.6 fold increase of trkB tyrosine phosphorylation. There is also a simultaneous improvement of exon III BDNF and trkB mRNA levels, respectively, by 3 and 2 folds in the rat hippocampus. The rats treated with the peptide displayed a significant increase in the number of conditioned avoidance reactions. The findings indicate the influence of the peptide in improving cognitive brain functions through the hippocampal BDNF/trkB system.
Semax Improves Memory in Studies.
Semax and mexidol act as effective antiamnesic medication for murine models of amnesia (except that induced by maximal electroshock) compared to reference nootropic drugs like piracetam and oxiracetam. Semax displays a bell-shaped reversible dose-effect equation while Mexidol has a linear relationship. Both the substances helped suppress the ortho-and antidromic population response surges of CA1 pyramidal neurons of survival hippocampal slices in rats. Interestingly, compared to semax, mexidol improves oxygen consumption in rat brain mitochondria and displays a linear dose-effect response in a 1-5 mM concentration range.
Protective Effects of Semax on Cerebral Blood Vessels During Oxygen Deprivation.
Intranasal use of Semax for six days reduced cortical infarction level, thus enhancing retention and performance of conditioned passive avoidance response. Semax decreases the levels of Vegfa mRNA in the frontal cortex (4, 8, and 12 h following occlusion) and the hippocampus (2 and 4 h post occlusion). The Effect of PGP on the Vegfa gene expression was almost negligible. Semax prevents hypoxia-induced Vegfa gene expression at the 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 highlights the neuroprotective properties of the peptide.
The VEGF-b and Vegf-d genes were most regulated by the peptides causing noticeable activation at three h after pMCAO. The level of VEGF-d transcripts decreased significantly, whereas the mRNA level of the Vegf-b gene was significantly increased post 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. Thus the peptides reduce the effects of ischemia, thereby enhancing the positive therapeutic effect of semax on ischemic stroke.
Semax also alters the expression of several genes in the vascular system. The expression of 24 and 12 genes was altered 3 and 24 hours after pMCAO, respectively. Semax was observed to promote vessel formation and stabilization post 24 hours of occlusion. It also affected the activation of blood cells around 24 h after pMCAO, which followed logically after forming blood cells induced by Semax 3 h after the occlusion. Histological studies validated the same findings whereby Semax and PGP improved neuroglia, blood vessel endothelium, and progenitor cells in the subventricular zone. Semax in a dose of 0.3 mg/kg prevented neurological disturbances and excess NO production in the rat brain cortex.
The Effect of semax on the Morphology and Proliferative Activity of Rat Brain Cells During Oxygen Deprivation.
Going by available literature (Cherkasova et al. 2001), the antithrombotic and anticoagulant action of Semax ameliorates ischemic damage. Semax prevents aggregation and formation of erythrocyte debris in the microcirculatory channels, leading to reduced brain blood perfusion. It helps in nervous tissue oxygenation and prevents secondary destructive reactions. Second, increased PCNA expression in the cell nuclei of ependymocytes, neuroglia, and blood vessel endothelium post semax administration to animals of both control and experimental groups proves semax stimulated cells to be directly involved trophic supply of the CNS.
The Peptide Activates Many Cytokines and Gene Expressions of the Immune System.
Semax induces the majority of the immune-response genes; among these, especially immunoglobulin genes, half of them show maximum expression changes.
“The neuroprotective and nootropic roles of semax are not restricted to nervous tissues but extend to the immune system as well. Semax acted on microglia and immune system cells three hours after pMCAO. It influenced leukocyte activation most significantly. The peptide also affected DCs, which are a heterogeneous class of antigen-presenting cells that are capable of immune response initiation and cytokine production.
Both inflammation and immune response regulate ischemic stroke. The penetration of inflammatory/immune cells into brain tissues during the postischemia hours aggravates the situation. In addition, there is lacking evidence 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.
Twenty-four hours after pMCAO, immunoglobulin expression was highest in the ischemic rat brain cortex. Several studies have shown that intravenous immunoglobulin (IVIG) has a solid neuroprotective influence against ischemic impairment of the brain.
Response of the vascular system to the administration of the neuropeptide.
The expression of many genes involved in the functioning of the vascular system gets influenced by semax administration. The formation of new blood vessels in the ischemic areas helps to treat brain stroke. 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. Moreover, diverse genes are expressed in both endothelial cells and hematopoietic precursor cells of the adult organism. Three hours post occlusion, semax altered the expression of genes associated with the artery vasodilation process also. Evidence showed that semax is likely to influence processes that accompany the formation of new blood vessels during early ischemia cascade stages and their stabilization at later stages. Semax also influenced blood cell activation about 24 h after pMCAO, which followed logically after the process of the blood cell formation induced by semax three h after the occlusion.
Semax Protects Neurons From Glutamate-induced Cell Death Despite Promoting Calcium Accumulation Inside Cells.
Semax influences the expression of genes that regulate the levels of Ca2+ 24 h after occlusion. The peptide increased both the amount and mobility of immune cells and the expression of chemokine and immunoglobulin genes.
It is well known that ischemia-induced energy depletion in cells results in the disturbing 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. The neuroprotective effect of semax on ischemia-damaged nervous tissues may include the impact of Ca2+ penetration into the cell on the regulatory processes.
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 about 30%. The neuroprotective effect of semax in cerebral ischemia/hypoxia can be due to the improvement of mitochondrial resistance to “calcium” stress.
An ACTH (4-10) Analogue with Nootropic Properties, Activates Dopaminergic and Serotoninergic Brain Systems in Rodents.
The tissue content of 5-hydroxy indole acetic acid (5-HIAA) in the striatum was considerably increased two h after semax administration. The extracellular striatal level of 5-HIAA also gradually increased within 1–4 h after semax administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites, but when injected 20 min prior to D:
-amphetamine dramatically enhanced the latter’s effects on the extracellular level of dopamine and the locomotor activity of animals.
Semax is a Potential Agent for ADHD and Rett syndrome.
It can enhance the effects of psychostimulants on central dopamine release and trigger central brain-derived neurotrophic factor (BDNF) synthesis. In addition, it 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 that semax may have good therapeutic potential in ADHD. Furthermore, increased BDNF activity is found to improve Rett syndrome. In most cases, this severe neurodevelopmental disorder is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2).
Protective Effect of Peptide Semax on the Rat Heart Rate After Heart Damage.
The peptide did not affect cardiac work but partially blocked end-diastolic pressure growth in the left ventricle and ameliorated cardiomyocyte hypertrophy and disproportionate growth of contractile and mitochondrial apparatus. It thus mediated beneficial effect on the left ventricular remodeling and heart failure development late after myocardial infarction.
Protective Ability Against Metal Induced Cell Toxicity and High Affinity for Copper II ions.
Semax induces reduced copper-induced cytotoxicity as observed in the presence of the peptide by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay on SHSY5Y neuroblastoma and RBE4 endothelial cell lines.
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 the organization and in multiple tissues, including both the brain and periphery. The chronic administration of semax 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 decreased 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.
Boosts Endorphins by Inhibiting the Enkephalin-Degrading Enzymes.
Semax and Selank have a dose-dependent effect on the enkephalin-degrading enzymes of human serum. Semax (IC5010 μM) and Selank (IC5020 μM) show more pronounced effects than that of puromycin (IC5010 mM), bacitracin, and some other inhibitors of peptidases.
Inhibits Histamine Release from Mast Cell Activation.
Semax, Selank, PGPL FPG, GPG, PG, and GP suppressed the secretion of histamine from mast cells and increased the vascular permeability after the administration of Synacthen and LPS.
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.
Semax Stimulates Acetylcholine and Exploratory Activity.
The molecule improves the survival of cholinergic basal forebrain neurons in vitro. It further stimulated choline acetyltransferase activity in dissociated basal forebrain tissue cultures without affecting the number of GABA-ergic neurons.
Semax in Glaucomatous Optic Neuropathy in Patients with Normalized Ophthalmic Tone.
A complex of neuroprotective therapy, including semax, was used to treat glaucoma patients with normalized ophthalmic tone. Electrophysiological and computer methods of examination demonstrated the advantages of new therapy over traditional neuroprotective treatment. The efficiency is due to the pathogenetic activity of semax possessing both neuroprotective and neurotrophic effects.
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