Semax Peptide

Semax is a synthetic polypeptide derived from a fragment of adrenocorticotropic hormone (ACTH 4–7),(1) which is normally secreted by the anterior pituitary gland. This specific fragment is not thought to exhibit the classical hormonal effects of ACTH but is instead proposed to have more targeted actions within the brain.(2)

Naturally occurring peptides are often unstable and prone to rapid degradation by enzymes present in biological environments such as the gastrointestinal tract and cerebrospinal fluid. To address this, synthetic analogues like Semax have been developed to retain potential biological activity while improving stability. Structurally, Semax consists of the Met-Glu-His-Phe sequence extended with a Pro-Gly-Pro (PGP) motif at the C-terminus.

The addition of the PGP sequence is proposed to enhance the peptide’s ability to cross the blood–brain barrier (BBB), potentially by increasing its lipophilicity. This may facilitate transport into the brain through mechanisms such as passive diffusion or lipid raft-mediated endocytosis, which can bypass the restrictive tight junctions of the BBB. Additionally, the PGP motif may influence interactions with transporters or receptors, possibly enabling receptor-mediated transcytosis.

Further structural modifications, such as acetylation, are thought to improve the peptide’s resistance to enzymatic degradation, thereby extending its half-life and stability in biological systems. These combined features make Semax a peptide of interest in research exploring central nervous system activity and peptide-based signalling.

Overview

Synthetically developed Semax has been extensively studied for its potential mechanisms of action and is often noted for its enhanced biological stability. Researchers suggest that Semax may inhibit certain enzymes responsible for degrading enkephalins—endogenous neurotransmitters involved in processes such as pain perception (nociception) and stress response. By potentially increasing enkephalin levels, Semax may indirectly influence other neurotransmitter systems, including dopamine and serotonin, due to the interconnected nature of the opioid and monoaminergic systems. These interactions may involve modulation of neurotransmitter release, receptor activity, and downstream signalling pathways, reflecting a complex neurochemical network that remains under active investigation.

In addition to its effects on enkephalins, Semax has also been explored for its influence on other peptide-degrading enzymes, suggesting a broader regulatory role in neuropeptide stability. One study(4) indicated that Semax may promote increased release of dopamine and elevate levels of brain-derived neurotrophic factor (BDNF), a protein associated with neuronal growth and synaptic plasticity. Another study(5) proposed that Semax may alter gene expression related to immune system function, potentially affecting immune cell activity and mobility.

Furthermore, researchers have reported that Semax may influence the expression of genes involved in chemokine and immunoglobulin production, which are linked to immune and vascular system function. These findings suggest that Semax may have multifaceted biological effects spanning neurochemical signalling, neuroplasticity, and immune regulation, although the precise mechanisms and clinical relevance remain to be fully established.

Chemical Makeup
  • Molecular Formula: C39H54N10O10S
  • Molecular Weight: 854.99 g/mol
  • Other Known Titles: ACTH (4-7)PGP, HY-P1146
Research Studies and Clinical Trials
Semax Peptide and Nootropic Action

An early study(6) investigating ACTH analogues, including Semax, explored its potential nootropic effects in murine models. Following peptide exposure, researchers monitored levels of 5-hydroxyindoleacetic acid (5-HIAA), the primary metabolite of serotonin. Results indicated that 5-HIAA levels increased by approximately 25% within 2 hours and continued to rise, reaching up to 180% after 4 hours of Semax exposure.

Additionally, when Semax was administered 20 minutes prior to D-amphetamine, a further elevation in 5-HIAA levels was observed compared to Semax alone. Since 5-HIAA reflects serotonin metabolism, these findings suggest that Semax may enhance serotonergic activity.

This proposed influence on serotonin pathways may have downstream effects on central nervous system functions, including mood, cognition, and overall neural processing. However, these mechanisms remain theoretical and require further investigation to fully understand their implications.

Semax Peptide and Neonatal Anxiety Models

The primary aim of this study(7) was to investigate the interaction between an SSRI and Semax in neonatal murine models. In the experiment, models aged 1–14 days were first exposed to an SSRI, followed by administration of Semax from days 15 to 28. After the full 28-day period, researchers observed that early SSRI exposure appeared to induce anxiety-like behaviours, along with impaired responses to stress and novel stimuli.

Following subsequent exposure to Semax, these effects appeared to be mitigated. The models demonstrated reduced anxiety-related behaviours and, notably, improvements in learning performance. Researchers proposed that Semax may have contributed to restoring normal levels of monoamine neurotransmitters—such as serotonin, dopamine, and norepinephrine—which may have been disrupted by the SSRI.

Through modulation of these neurotransmitter systems, Semax may help rebalance excitatory and inhibitory signalling within the brain. Increased serotonin activity may support improved mood and reduced anxiety, while dopamine modulation may enhance motivation and reward processing. Adjustments in norepinephrine signalling may contribute to improved attention and alertness.

Importantly, behavioural assessments suggested that these effects were not only immediate but also sustained over time. Reductions in anxiety-like behaviours persisted from adolescence into early adulthood, indicating that Semax may have a lasting influence on neural circuitry. These findings suggest a potential role for Semax in supporting long-term stabilisation or correction of disrupted neurochemical pathways, although further research is required to confirm these mechanisms.

Semax Peptide and the Vascular System

In this study,(8) researchers evaluated the potential of Semax to protect cardiac tissue in murine models following experimentally induced myocardial infarction (MI). After inducing MI, one group of models was treated with Semax over a period of six days, while a control group received no such intervention.

By day 28, the control group appeared to develop signs of cardiac hypertrophy along with reduced arterial blood pressure. In contrast, the Semax-exposed group showed indications of improved cardiac outcomes, including prevention of diastolic pressure increase in the left ventricle and signs of adaptive left ventricular remodeling.

Additionally, Semax exposure was associated with a reduction in cardiomyocyte hypertrophy and an apparent improvement in the balance between contractile structures and mitochondrial components within cardiac cells. These findings suggest that Semax may influence cardiac structural adaptation following injury, although further research is needed to fully understand the mechanisms and clinical relevance of these effects.

Semax Peptide and Neonatal Deprivation

In this study,(9) adolescent rats were subjected to maternal separation for approximately 5 hours per day during postnatal days 1 to 14. This early-life stress model was used to induce anxiety-like and heightened emotional reactivity. From days 15 to 28, the rats were then exposed to the Semax peptide.

Following the full 28-day period, researchers observed that rats experiencing maternal deprivation without intervention exhibited increased anxiety and heightened physical and emotional responsiveness. However, in the group exposed to Semax, these behaviours appeared to return toward levels comparable to control models.

These findings suggest that Semax may influence behavioural responses associated with early-life stress, potentially supporting normalization of anxiety-related and emotional reactivity patterns, although the underlying mechanisms remain to be fully understood.

Semax Peptide and Neuroprotection

This clinical trial(10) involved 100 research models with ischemic stroke, with approximately 30% of the subjects receiving Semax while the remaining served as a control group. Following the intervention, researchers reported that the Semax-exposed group appeared to show an improved rate of recovery in neurological function compared to controls.

These outcomes were assessed using electroencephalography (EEG) mapping, which indicated changes associated with functional restoration of brain activity. The findings suggest that Semax may influence post-stroke neurological recovery processes, although further research is required to confirm these effects and better understand the underlying mechanisms.

Semax Peptide and Nootropic Properties

A small-scale clinical trial(11) examined the effects of Semax under conditions of elevated stress, with brain activity monitored throughout the experiment. After a 24-hour period, researchers reported that, compared to baseline pre-trial measurements, the subjects appeared to demonstrate improved memory recall and increased attention or focus intervals.

These findings suggest that Semax may influence cognitive performance under stress, particularly in areas related to memory and concentration, although further research is required to validate these observations and clarify the underlying mechanisms.

Semax peptide is available for research and laboratory purposes only. Please speak to our friendly research team to find out more and for sourcing options.

References:

  1. T. Kolomin et al., A New Generation of Drugs: Synthetic Peptides based on Natural Regulatory peptides. Neuroscience & Medicine, 2013, 223-252. Published Online December 2013.  http://dx.doi.org/10.4236/nm.2013.44035

  2. Dornbush RL, Nikolovski O. ACTH 4-10 and short-term memory. Pharmacol Biochem Behav. 1976;5(Suppl 1):69-72. doi: 10.1016/0091-3057(76)90331-2. PMID: 189333.  https://pubmed.ncbi.nlm.nih.gov/189333/

  3. Kost NV, Sokolov OIu, Gabaeva MV, Grivennikov IA, Andreeva LA, Miasoedov NF, Zozulia AA. Ingibiruiushchee deĭstvie semaksa i selanka na énkefalindegradiruiushchie fermenty syvorotki krovi cheloveka [Semax and selank inhibit the enkephalin-degrading enzymes from human serum]]. Bioorg Khim. 2001 May-Jun;27(3):180-3. Russian. doi: 10.1023/a:1011373002885. PMID: 11443939.  https://pubmed.ncbi.nlm.nih.gov/11443939/

  4. Shih-Jen Tsai, Semax, an analogue of adrenocorticotropin (4–10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndrome, Medical Hypotheses, Volume 68, Issue 5, 2007, Pages 1144-1146.  https://doi.org/10.1016/j.mehy.2006.07.017

  5. Medvedeva, E.V., Dmitrieva, V.G., Povarova, O.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 15, 228 (2014).  https://doi.org/10.1186/1471-2164-15-228

  6. Eremin KO, Kudrin VS, Saransaari P, Oja SS, Grivennikov IA, Myasoedov NF, Rayevsky KS. Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochem Res. 2005 Dec;30(12):1493-500.  doi: 10.1007/s11064-005-8826-8. PMID: 16362768.

  7. Nataliya Yu. Glazova, Daria M. Manchenko, Maria A. Volodina, Svetlana A. Merchieva, Ludmila A. Andreeva, Vladimir S. Kudrin, Nikolai F. Myasoedov, Natalia G. Levitskaya, Semax, synthetic ACTH(4–10) analogue, attenuates behavioural and neurochemical alterations following early-life fluvoxamine exposure in white rats, Neuropeptides, Volume 86, 2021, 102114, ISSN 0143-4179.  https://doi.org/10.1016/j.npep.2020.102114

  8. Gavrilova SA, Golubeva AV, Lipina TV, Fominykh ES, Shornikova MV, Postnikov AB, Andrejeva LA, Chentsov IuS, Koshelev VB. [Protective effect of peptide semax (ACTH(4-7)Pro-Gly-Pro) on the rat heart rate after myocardial infarction]. Ross Fiziol Zh Im I M Sechenova. 2006 Nov;92(11):1305-21. Russian. PMID: 17385423.  https://pubmed.ncbi.nlm.nih.gov/17385423/

  9. Volodina MA, Sebentsova EA, Glazova NY, Levitskaya NG, Andreeva LA, Manchenko DM, Kamensky AA, Myasoedov NF. Semax attenuates the influence of neonatal maternal deprivation on the behavior of adolescent white rats. Bull Exp Biol Med. 2012 Mar;152(5):560-3. English, Russian. doi: 10.1007/s10517-012-1574-2. PMID: 22803132.  https://pubmed.ncbi.nlm.nih.gov/22803132/

  10. Gusev EI, Skvortsova VI, Miasoedov NF, Nezavibat'ko VN, Zhuravleva EIu, Vanichkin AV. Effektivnost' semaksa v ostrom periode polusharnogo ishemicheskogo insul'ta (klinicheskoe i élektrofiziologicheskoe issledovanie) [Effectiveness of semax in acute period of hemispheric ischemic stroke (a clinical and electrophysiological study)]. Zh Nevrol Psikhiatr Im S S Korsakova. 1997;97(6):26-34. Russian. PMID: 11517472.  https://pubmed.ncbi.nlm.nih.gov/11517472/

  11. Asmarin IP, Nezavibat'ko VN, Miasoedov NF, Kamenskiĭ AA, Grivennikov IA, Ponomareva-Stepnaia MA, Andreeva LA, Kaplan AIa, Koshelev VB, Riasina TV. Nootropnyĭ analog adrenokortikotropina 4-10-semaks (15-letniĭ opyt razrabotki i izucheniia) [A nootropic adrenocorticotropin analog 4-10-semax (l5 years experience in its design and study)]. Zh Vyssh Nerv Deiat Im I P Pavlova. 1997 Mar-Apr;47(2):420-30. Russian. PMID: 9173745.  https://pubmed.ncbi.nlm.nih.gov/9173745/

Dr. Marinov

Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.

Semax Peptide