Key Takeaways
- •Research indicates that Semax exhibits marked antiamnesic effects across various models of amnesia in mice, with the exception of amnesia induced by maximal electroshock.
- •Studies demonstrate that intranasal administration of Semax for six days significantly decreased the volume of cortical infarction in animal models.
- •Investigations into gene expression reveal that Semax treatment reduces levels of Vegfa mRNA in the frontal cortex at 4, 8, and 12 hours post-occlusion, as well as in the hippocampus at 2 and 4 hours post-occlusion.
Semax and Memory Enhancement: Evidence from Preclinical Amnesia Models
Research indicates that Semax exhibits marked antiamnesic effects across various models of amnesia in mice, with the exception of amnesia induced by maximal electroshock. In comparative studies, the antiamnesic profile of Semax was found to be comparable to that of the reference nootropic agents piracetam and oxyracetam. Notably, Semax demonstrated a bell-shaped reversible dose-effect relationship, a characteristic distinct from the linear relationship observed with mexidol. In electrophysiological investigations using survival hippocampal slices from rats, both Semax and mexidol inhibited ortho- and antidromic population response spikes of CA1 pyramidal neurons. Additionally, unlike mexidol—which increased oxygen consumption in rat brain mitochondria with a linear dose-effect relationship in a 1–5 mM concentration range—Semax did not exhibit this effect (23).
Vascular Protective Effects of Semax During Oxygen Deprivation
Studies demonstrate that intranasal administration of Semax for six days significantly decreased the volume of cortical infarction in animal models. This treatment also improved the retention and performance of conditioned passive avoidance responses (10).
Investigations into gene expression reveal that Semax treatment reduces levels of Vegfa mRNA in the frontal cortex at 4, 8, and 12 hours post-occlusion, as well as in the hippocampus at 2 and 4 hours post-occlusion. In contrast, the effect of the Pro-Gly-Pro (PGP) fragment on Vegfa gene expression was almost negligible. These findings suggest that Semax prevents the activating effect of hypoxia on Vegfa gene expression during the early stages of global cerebral ischemia. Interestingly, an increase in Vegfa mRNA levels in the hippocampus 24 hours after occlusion following Semax administration is believed to reflect the neuroprotective properties of the peptide (1).
Further analysis indicates that the Vegf-b and Vegf-d genes were most affected by the peptides, with notable activation observed at 3 hours after permanent middle cerebral artery occlusion (pMCAO). At 72 hours post-treatment, the level of Vegf-d transcripts decreased considerably, while Vegf-b mRNA levels were significantly increased by each peptide. Importantly, the effects of the peptides on Vegf-b and Vegf-d expression were opposite to the action of ischemia itself. Researchers suggest that these identified effects diminish the impact of ischemia, thereby contributing to the positive therapeutic effect of Semax on ischemic stroke (1).
Another significant group of genes with Semax-induced expression alterations includes those involved in the vascular system. The expression of 24 genes was altered at 3 hours post-pMCAO, and 12 genes were affected at 24 hours post-pMCAO (2). Histological analysis at 24 hours post-occlusion showed that Semax affected the development of endothelial tissue and the migration of smooth muscle cells, indicating vessel formation and stabilization. Additionally, the activation of blood cells was influenced by Semax 24 hours after pMCAO, a process that logically follows the formation of blood cells induced by Semax 3 hours after occlusion (2).
For the first time at the histological level, research has shown that Semax and PGP increased proliferation of neuroglia, blood vessel endothelium, and progenitor cells in the subventricular zone (9).
A clear correlation has been observed between nitric oxide (NO) content in the rat brain and the level of neurological disturbance manifestations in ischemized animals. Semax, a synthetic peptide fragment of ACTH4-7 (Pro-Gly-Pro), administered at a dose of 0.3 mg/kg, prevented the development of both neurological disturbances and excess NO production in the rat brain cortex (19).
Semax Effects on Brain Cell Morphology and Proliferation During Hypoxia
Research suggests that Semax provides a histologically verifiable neuroprotective action by alleviating symptoms of vascular stasis during disturbances in brain blood circulation. According to available data, the antithrombotic and anticoagulant action of Semax may play a significant role under conditions of ischemic damage. By preventing the aggregation and formation of erythrocyte debris in microcirculatory channels—which can lead to reduced brain blood perfusion—Semax is likely to contribute to nervous tissue oxygenation and hinder the development of secondary destructive reactions. Furthermore, increased PCNA expression in the cell nuclei of ependymocytes, neuroglia, and blood vessel endothelium following Semax administration to both control and experimental groups testifies to the stimulatory effect of this peptide on cells directly involved in the trophic supply of the central nervous system.
Semax Modulation of Cytokine and Immune System Gene Expression
Studies indicate that Semax-induced upregulation of transcripts was observed for a majority of immune-response genes. Among these, immunoglobulin genes formed the most prominent group, with half of them exhibiting the highest amplitude of expression alteration among all genes affected by the peptide (16).
Historically, the neuroprotective and nootropic properties of Semax were associated only with events directly relevant to nervous tissues. However, recent research has 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 hours after pMCAO, involving leukocytes, remained significant. Additionally, Semax affected dendritic cells (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 capable of immune response initiation and cytokine production.
Both inflammation and immune response play an important role in ischemic stroke. While penetration of inflammatory/immune cells into brain tissues during post-ischemia hours can aggravate the situation, some studies also support the neuroprotective abilities of immune cells. Notably, the most noticeable immune response to Semax action was observed at 24 hours after pMCAO, with a high level of immunoglobulin transcripts found in the ischemized rat brain cortex. Several studies have previously shown that intravenous immunoglobulin (IVIG) has a strong neuroprotective effect against ischemic impairment of the brain (16).
Semax and the Vascular System Response
Research has identified 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 ischemized areas represents one approach used in the treatment of 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. Some signaling pathways are known to be active in both hematopoiesis and vasculogenesis, and a large number of genes are expressed in both endothelial cells and hematopoietic precursor cells of the adult organism. Three hours after occlusion, Semax also altered the expression of genes associated with the artery vasodilation process. Earlier studies showed that capillary bore extension was observed as early as 15 minutes after administration of the peptide. These data suggest 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, the activation of blood cells was affected by Semax 24 hours after pMCAO, following logically from the formation of blood cells induced by Semax 3 hours after occlusion (15).
Semax, Calcium Homeostasis, and Glutamate-Induced Neuronal Death
Genes that regulate the levels of Ca²⁺ formed a separate group exhibiting significant Semax-induced alteration of expression 24 hours after occlusion. The peptide increased the amount and mobility of immune cells and enhanced the expression of chemokine and immunoglobulin genes (16).
Research results show that Semax enhanced the expression of genes encoding protein products that promote intracellular Ca²⁺ accumulation. It is hypothesized that the neuroprotective effect of Semax on ischemia-damaged nervous tissues may include an impact on processes involved in the incorporation of Ca²⁺ into cells (16).
Ischemia-induced energy depletion in cells results in disturbed operation of potential-dependent calcium channels and Na⁺/Ca²⁺ pumps, leading to excessive intracellular accumulation of Ca²⁺ ions and neuronal death. However, studies have shown that Semax contributes to neuron survivability under 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 alone. The neuroprotective effect of Semax on ischemia-damaged nervous tissues may therefore include an impact of Ca²⁺ penetration into the cell on regulatory processes, an idea supported by recent studies of the neuroprotective effect of Ca²⁺-activated potassium channels in conditions of brain ischemic damage (16).
Semax Effects on Calcium Dysregulation and Mitochondrial Potential
Research demonstrates that Semax (100 µM) and its Pro-Gly-Pro fragment (20 and 100 µM) delayed the development of calcium dysregulation and reduction of mitochondrial potential in cultured cerebellar granule cells under conditions of glutamate neurotoxicity. Incubation with these peptides improved neuronal survival by an average of 30%. The neuroprotective effect of Semax in cerebral ischemia/hypoxia may be due to improvement of mitochondrial resistance to "calcium" stress (8).
Semax Activation of Dopaminergic and Serotoninergic Systems
As an ACTH(4-10) analogue with nootropic properties, Semax has been shown to activate dopaminergic and serotoninergic brain systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 hours after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1–4 hours after Semax (0.15 mg/kg, ip) administration. While Semax alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites, Semax injected 20 minutes prior to D-amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals (7).
Semax as a Potential Research Agent for ADHD and Rett Syndrome
Research suggests that Semax can augment the effects of psychostimulants on central dopamine release and also stimulates central brain-derived neurotrophic factor (BDNF) synthesis. Additionally, Semax may improve selective attention and modulate brain development. Since attention deficit hyperactivity disorder (ADHD) is likely to be a neurodevelopmental disorder with disturbance in dopamine and BDNF function, it has been proposed that Semax may have good therapeutic potential in ADHD research. Furthermore, increased BDNF activity is found to improve Rett syndrome, a severe neurodevelopmental disorder which, in the majority of cases, is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) (22).
Protective Effect of Semax on Cardiac Function After Heart Damage
Studies indicate that while Semax did not affect cardiac work, it partially prevented end-diastolic pressure growth in the left ventricle. The peptide also ameliorated cardiomyocyte hypertrophy and disproportionate growth of contractile and mitochondrial apparatus, thus exerting a beneficial effect on heart rate regulation following cardiac damage.
Reviewed by the Volta Peptides Research Team