Semax Peptide Spray

Semax Intranasal Research Tab
Semax Intranasal Research & Scientific Overview

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Semax Molecular Structure & Chemical Properties

Semax represents one of the most thoroughly investigated synthetic neuropeptides in preclinical and limited clinical research, with over three decades of study spanning cognitive function, cerebrovascular protection, and neurotrophin regulation. Developed in the 1980s through collaborative work between the Institute of Molecular Genetics of the Russian Academy of Sciences and Moscow State University, this seven-amino acid peptide (Met-Glu-His-Phe-Pro-Gly-Pro) was engineered as a stable analog of adrenocorticotropic hormone (ACTH) fragment 4-10, retaining its neurotrophic activity while eliminating hormonal side effects. Unlike native ACTH fragments – which have a duration of action as short as 30-60 minutes – the addition of the C-terminal Pro-Gly-Pro tripeptide significantly extends biological activity in animal models. Semax’s compact heptapeptide structure and resistance to enzymatic degradation have made it a practical candidate for intranasal delivery research, as the nasal route allows rapid CNS penetration without requiring parenteral administration.

Chemical Structure

[IMAGE PLACEHOLDER] Insert 2D chemical structure image here Image URL: https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=9811102&t=l Alt text: Semax 2D molecular structure diagram showing heptapeptide sequence Source credit: PubChem Position: Center-aligned below “Chemical Structure” heading

2D molecular structure (Source: PubChem)

Technical Specifications

Property

Value

CAS Number

80714-61-0

Molecular Formula

C37H51N9O10S (subscripted)

Molecular Weight

813.93 g/mol

Amino Acid Sequence

Met-Glu-His-Phe-Pro-Gly-Pro

Half-Life (Plasma)

Rapid degradation; CNS detection within 2 minutes of intranasal dosing (rat models)

Stability

Resistant to enzymatic degradation relative to native ACTH fragments; stable in lyophilized form

Solubility

Water soluble; suitable for saline-based nasal formulations

Storage

Lyophilized: -20 degrees C; Reconstituted solution: 2-8 degrees C

The peptide’s histidine and methionine residues contribute to its copper-chelating properties, which have been studied in the context of amyloid aggregation models, adding a structural dimension relevant to neurodegenerative research.

Semax Mechanism of Action

Semax exerts its effects through several interconnected neurobiological pathways rather than a single defined receptor, and the complete molecular mechanism of action remains an active area of investigation. Current evidence points to neurotrophin gene regulation as a primary driver of its observed neuroprotective and cognitive effects in animal models, supported by modulatory activity across neurotransmitter systems, melanocortin receptors, and inflammatory signaling networks.

Primary Cellular Pathways
BDNF and NGF Upregulation – Neurotrophin Signaling

The most consistently replicated mechanistic finding is Semax’s ability to rapidly induce expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Studies in rat glial cell cultures demonstrated that Semax caused rapid induction of BDNF and NGF mRNA transcription within 30 minutes of administration[1]. Intranasal administration in intact rats produced two peaks of BDNF and NGF gene expression – the first at approximately 1.5 hours and the second, larger peak at approximately 8 hours after administration in the hippocampus and frontal cortex[2]. Key findings include:

Increased BDNF and TrkB (the primary BDNF receptor) protein and mRNA levels in the rat hippocampus
NGF upregulation in the frontal cortex and retina in addition to hippocampal regions
Activation of downstream MAPK/ERK and PI3K/Akt signaling cascades through TrkB receptor engagement
Persistent neurotrophin effects lasting beyond the peptide’s rapid plasma clearance
Melanocortin Receptor Modulation

Research indicates Semax may act at melanocortin receptors, specifically MC4 and MC5, behaving as a competitive antagonist or partial agonist of alpha-melanocyte-stimulating hormone (alpha-MSH) at these receptors in both in vitro and in vivo conditions[3]. This is mechanistically significant because alpha-MSH itself exerts anti-inflammatory, neurogenic, and neuroprotective effects, and Semax may recapitulate aspects of this activity through receptor modulation. The MC3 receptor has also been proposed as a potential target, though assay data for MC1 and MC2 remain absent from the literature.

Monoaminergic System Modulation

Animal studies have documented that Semax modulates both serotonergic and dopaminergic neurotransmission. Research showed that tissue levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum were significantly increased approximately 2 hours after Semax administration[4]. Additionally:

Semax potentiated the locomotor-stimulating effects of D-amphetamine in rodent models, suggesting dopaminergic system interaction
Modulation of GABAergic and glycinergic ionic currents has been documented in isolated cerebral neurons
Serotonin – but not dopamine – levels were directly elevated following intranasal administration in rats
Enkephalinase Inhibition

Semax, along with the related peptide Selank, has been found to inhibit enzymes responsible for degrading enkephalins and other endogenous regulatory peptides (IC50 = 10 mcM)[5]. This enkephalinase inhibition may prolong the activity of endogenous opioid and regulatory peptides, though the clinical or research significance of this property remains incompletely characterized.

Immunomodulatory and Transcriptome Effects

Genome-wide transcriptional analyses in rat stroke models revealed that Semax exerts broad effects on immune gene expression, increasing the amount and mobility of immune cells and enhancing expression of chemokine and immunoglobulin genes[6]. These immunomodulatory effects, combined with effects on vascular gene expression, are considered potential contributors to its neuroprotective profile in ischemia research.

[CALLOUT BOX – Highlighted] Key Mechanistic Gap: Despite decades of research, Semax’s primary receptor or binding site has not been definitively identified. Its multi-pathway activity – spanning neurotrophins, monoamines, melanocortin receptors, and immune modulation – may represent either a genuinely pleiotropic mechanism or downstream effects from a single upstream target yet to be characterized. [END CALLOUT BOX]

Semax Research Applications & Key Findings
Cerebrovascular and Stroke Research
Ischemia and Infarct Volume Reduction

The most extensively studied application of Semax in preclinical research involves cerebral ischemia models. Intranasal administration of Semax (250 mcg/kg) across six daily treatments after photothrombotic injury reduced infarct volume and improved performance on a passive avoidance task in rats[7]. Additional findings in ischemia models include:

Reduced neurological deficiency in the first 6.5 hours after global ischemia surgery, with improved survival rates in treated rodents
Decreased production of nitric oxide in the cerebral cortex following incomplete global ischemia, suggesting antioxidant protection[8]
Activation of vasculogenesis-related gene expression within 3 hours of middle cerebral artery occlusion
Improved performance on neurobehavioral assessments in models of cerebral ischemia caused by gravitational overload
Limited Human Stroke Data

Semax is registered in Russia for acute ischemic stroke and has been studied in Russian clinical settings. One study in 110 patients following ischemic stroke examined two 10-day courses of intranasal Semax at 6,000 mcg/day with a 20-day interval[9]. Investigators reported increased plasma BDNF levels that remained elevated throughout the study period, along with improved motor performance and Barthel index scores – a measure of functional independence – in the Semax group. A separate earlier trial reported improved neurological function when Semax was added to standard care. These studies are limited by their origin in Russian-language journals, with some available only as abstracts or without full peer-reviewed English publications, constraining independent evaluation.

Cognitive Function Research
Animal Models

In healthy rat models, intranasal and intraperitoneal Semax improved performance on passive avoidance tasks – a measure of learning and memory retention – within 15 minutes of administration[10]. Research in humans, while scarce, has included:

A study in healthy but cognitively fatigued subjects showing that a single intranasal dose at 16 mcg/kg produced a 71% accuracy rate on a memory test, compared to 41% in the control group, with effects lasting 24 hours
An fMRI study in 24 healthy middle-aged subjects demonstrating increased resting-state signal in the default mode network’s rostral subcomponent following intranasal 1% Semax solution relative to placebo[11]
Electroencephalographic studies showing changes consistent with patterns observed with other neuroprotective compounds
Attention and Focus Mechanisms

Research has proposed Semax as a candidate for studying attention-deficit conditions given its dopaminergic and BDNF-related properties[12]. Preclinical data indicate Semax improves selective attention in rodent models, and its ability to augment central dopamine release in response to psychostimulants has been documented in animal studies. No human clinical trials for attention-related indications have been completed and published in peer-reviewed literature outside Russia.

Ophthalmic Research

Semax has been investigated in glaucomatous optic neuropathy in patients with normalized intraocular pressure in Russian clinical settings. Limited published data suggest potential protective effects on the optic nerve, consistent with the documented NGF upregulation in rat retinal tissue after intranasal dosing. This remains an area requiring independent replication.

Neuroprotection Against Toxic Stress

In vitro studies using cultured cerebellar granule cells demonstrated that Semax (100 mcM) delayed the onset of calcium dysregulation and mitochondrial potential reduction under glutamate neurotoxicity conditions, improving neuronal survival by approximately 30%[13]. Semax has also been studied for its ability to form stable copper complexes and inhibit copper-induced amyloid-beta aggregation and fibrillogenesis in artificial membrane models – a property relevant to Alzheimer’s disease research[14].

[CALLOUT BOX – Highlighted] Critical Research Context: While Semax has been used clinically in Russia for decades, the majority of human studies originate from Russian institutions, appear in Russian-language journals, and lack the methodological reporting required for systematic review inclusion. Western-validated human clinical trial data are extremely limited, making independent assessment of efficacy and safety difficult. [END CALLOUT BOX]

Semax Pharmacokinetics & Metabolism
Absorption & Distribution via Intranasal Route

Semax’s pharmacokinetics have been studied primarily in rat models using radiolabeled tritiated peptide. Following intranasal administration at 50 mcg/kg (20 mcl of solution), Semax was detectable in rat brain tissue within 2 minutes of administration[15]. Key distribution findings include:

Rapid CNS penetration – approximately 0.093% of total introduced radioactivity per gram detected in brain tissue at 2 minutes, with 80% remaining as intact Semax and 20% as metabolites at that early timepoint
Direct nose-to-brain transport via olfactory and trigeminal pathways, bypassing systemic circulation and the blood-brain barrier
Regional distribution favoring the hippocampus and basal forebrain, areas consistent with observed BDNF effects
Intranasal route produces detectable CNS levels more efficiently than would be predicted by systemic bioavailability alone
Metabolism & Elimination

Semax undergoes rapid enzymatic degradation in biological tissues, primarily through peptidase activity:

Primary metabolite is the C-terminal tripeptide Pro-Gly-Pro (PGP), which itself has been studied for independent biological activity in neurotrophin gene expression
Rapid metabolism in blood and peripheral tissues, consistent with the very short plasma half-life characteristic of peptide compounds
Despite rapid clearance from circulation, biological effects – particularly neurotrophin gene expression changes – persist for several hours to at least 8 hours after a single dose, suggesting durable downstream signaling
The disconnect between rapid peptide clearance and prolonged biological effects may reflect stable changes in gene transcription initiated by transient receptor interactions
Excretion Pathways

The excretion profile of Semax has not been fully characterized in published literature:

Likely renal elimination of peptide fragments and metabolites, consistent with small peptide pharmacokinetics generally
Hepatic metabolism may contribute to clearance through first-pass peptidase activity when administered systemically
No accumulation data available from chronic intranasal dosing studies
Excretion kinetics in species other than rodents remain unstudied in published literature
Semax Research Protocols & Administration
Dosing in Published Research

Doses reported in the Semax preclinical and clinical literature span a wide range depending on species, model, and route of administration:

Rat models (intranasal): 50 mcg/kg most common for mechanistic studies; 250 mcg/kg used in ischemia intervention models
Rat and mouse models (intraperitoneal): 50-250 mcg/kg range reported across neuroprotection and cognitive studies
Human clinical research (intranasal): 16 mcg/kg (single dose cognitive studies); 6,000 mcg/day (stroke rehabilitation protocols in Russian clinical research)

Important: These are experimental doses used in animal studies and cannot be extrapolated to other species due to significant differences in nasal mucosal anatomy, peptidase activity, receptor density, blood-brain barrier characteristics, and pharmacokinetic profiles between rodents and other species. Species-specific factors profoundly influence both observed effects and safety considerations.

Administration Routes in Research
Intranasal delivery – Primary route in both preclinical and clinical research; enables direct nose-to-brain transport; used as drops applied to nasal mucosa in published protocols
Intraperitoneal injection – Common in rodent studies for systemic delivery and pharmacokinetic characterization
Intravenous injection – Used primarily in pharmacokinetic and biodistribution studies
Subcutaneous injection – Reported in some Russian clinical and preclinical protocols
Common Model Organisms
Rats (Wistar, Sprague-Dawley, and non-inbred white strains) – Primary model for the majority of published Semax research including ischemia, cognition, and neurotrophin studies
Mice – Used for specific mechanistic studies including genetic knockout models
Cell culture – Rat glial cell cultures, cerebellar granule cell cultures, SH-SY5Y human neuroblastoma cells, RBE4 endothelial cells
Human subjects – Limited studies in stroke patients, healthy volunteers (Russia)
Research Limitations & Regulatory Status
Critical Gaps in Current Evidence

Despite three decades of research and clinical use in Russia, Semax faces substantial barriers to broader scientific acceptance due to significant gaps in independently replicated, peer-reviewed evidence.

Geographic Concentration and Language Barriers

A defining limitation of the Semax evidence base is its concentration in Russian-language literature:

The majority of published studies originate from a small number of Russian institutions
Many cited clinical studies exist only as Russian-language journal articles, conference abstracts, or without accessible full texts in international databases
Independent replication by Western research groups is largely absent
This geographic concentration makes systematic meta-analysis and independent quality assessment difficult
Mechanistic Understanding Gaps

Fundamental aspects of Semax’s mechanism remain unresolved:

Primary receptor or binding target has not been definitively identified despite decades of investigation
Whether melanocortin receptor interaction, neurotrophin induction, or enkephalinase inhibition represents the primary mechanism remains debated
The biological activity of the primary metabolite Pro-Gly-Pro complicates attribution of effects to parent peptide versus metabolite
Dose-response relationships have not been systematically characterized across species
Long-Term Safety Considerations

Critical safety questions have not been adequately investigated:

Long-term effects of repeated intranasal exposure are not characterized in peer-reviewed literature
Effects in specific populations (pediatric, elderly, immunocompromised) are not established in controlled research
Potential for downregulation of endogenous BDNF production with chronic use has not been examined
Interaction potential with medications affecting serotonergic, dopaminergic, or opioid systems is uncharacterized
Regulatory & Competitive Sport Status
FDA Position

Semax has not received FDA approval for any indication:

Not approved for human therapeutic use in the United States
Not classified as GRAS (Generally Recognized as Safe) for any application
No IND (Investigational New Drug) application data are publicly available from completed U.S.-based trials
Not legally available for medical compounding in the United States as an approved drug substance
Companies marketing Semax for human use in the U.S. face regulatory action
WADA Prohibition

The World Anti-Doping Agency prohibits Semax in competitive sport:

Listed under Section S0 (Non-Approved Substances) – prohibited at all times
No Therapeutic Use Exemptions (TUEs) are available given absence of regulatory approval in any WADA signatory country
Athletes subject to anti-doping testing should be aware that detection methods for peptide compounds continue to advance

Research Classification: Semax is available only for laboratory research use. It is not intended for human consumption, medical use, or veterinary applications. All research must be conducted under appropriate ethical oversight and regulatory compliance with institutional review board approval where applicable.

Lead Researcher Spotlight
Professor Nikolai F. Myasoedov, PhD

Head, Laboratory of Neuropeptides Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia

Professor Nikolai Myasoedov has been the central figure in Semax research since the peptide’s development in the 1980s, co-leading the team at the Institute of Molecular Genetics of the Russian Academy of Sciences that designed, synthesized, and characterized Semax as a stable analog of ACTH(4-10). His laboratory has been responsible for the foundational pharmacokinetic, neurotrophin-related, and translational work that forms the core of the published Semax evidence base. Professor Myasoedov has authored and co-authored a substantial portion of peer-reviewed English-language Semax publications spanning over three decades.

His primary research contributions to Semax science include:

Original development and characterization of Semax as a synthetic neuropeptide with extended biological half-life
Pharmacokinetic studies of intranasal Semax distribution in rat brain using radiolabeled peptide analogs
Neurotrophin gene expression studies documenting BDNF and NGF upregulation following Semax administration
Genome-wide transcriptomic analyses of Semax effects in rat stroke models
Translational research informing Semax’s registration as a pharmaceutical in Russia

Disclaimer: This spotlight is provided for educational purposes to acknowledge scientific contributions to Semax research. Cenexa Labs has no affiliation with Professor Myasoedov or the Institute of Molecular Genetics, Russian Academy of Sciences, and this information does not constitute an endorsement of any products or services.

References
Shadrina, M.I., Dolotov, O.V., Grivennikov, I.A., Slominsky, P.A., Andreeva, L.A., Inozemtseva, L.S., Limborska, S.A., & Myasoedov, N.F. (2001). Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neuroscience Letters, 308(2), 115-118. PubMed

Shadrina, M.I., Dolotov, O.V., Grivennikov, I.A., Inozemtseva, L.S., Limborska, S.A., & Myasoedov, N.F. (2010). Neurotrophin gene expression in the frontal cortex and hippocampus of rats after intranasal Semax administration. Journal of Molecular Neuroscience, 41(1), 1-7. Referenced in: Kolomin, T., Shadrina, M., Slominsky, P., Limborska, S., & Myasoedov, N. (2013). A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neuroscience & Medicine, 4, 223-252.

Dolotov, O.V., Karpenko, E.A., Inozemtseva, L.S., Seredenina, T.S., Levitskaya, N.G., Rozyczka, J., Dubynina, E.V., Novosadova, E.V., Andreeva, L.A., Alfeeva, L.Y., Kamensky, A.A., Grivennikov, I.A., Myasoedov, N.F., & Engele, J. (2006). Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research, 1117(1), 54-60. PubMed

Eremin, K.O., Kudrin, V.S., Saransaari, P., Oja, S.S., Grivennikov, I.A., Myasoedov, N.F., & Rayevsky, K.S. (2005). Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotonergic brain systems in rodents. Neurochemical Research, 30(12), 1493-1500. PubMed

Filippenkov, I.B., Stavchansky, V.V., Denisova, A.E., Yuzhakov, V.V., Sevan’kaeva, L.E., Sudarkina, O.Y., Dmitrieva, V.G., Gubsky, L.V., Myasoedov, N.F., Limborska, S.A., & Dergunova, L.V. (2020). Novel insights into the protective properties of ACTH(4-7)PGP (Semax) peptide at the transcriptome level following cerebral ischaemia-reperfusion in rats. Genes, 11(6), 681. PubMed

Dmitrieva, V.G., Povarova, O.V., Skvortsova, V.I., Limborska, S.A., Myasoedov, N.F., & Dergunova, L.V. (2010). Semax and Pro-Gly-Pro activate the transcription of neurotrophins and their receptor genes after cerebral ischemia. Cellular and Molecular Neurobiology, 30(1), 71-79. PubMed

Romanova, G.A., Shakova, F.M., Gudasheva, T.A., & Ostrovskaya, R.U. (2006). Impairment and recovery of cognitive function after frontal cortex photothrombotic lesion: the effect of noopept and semax. Bulletin of Experimental Biology and Medicine, 142(2), 199-202. PubMed

Bashkatova, V., Meunier, J., Maurice, T., & Vanin, A. (2001). Novel synthetic analogue of ACTH 4-10 (Semax) but not glycine prevents the enhanced nitric oxide generation in cerebral cortex of rats with incomplete global ischemia. Brain Research, 894(2), 145-152. PubMed

Gusev, E.I., Martynov, M.Y., Kostenko, E.V., Petrova, L.V., & Bobyreva, S.N. (2018). The efficacy of semax in the treatment of patients at different stages of ischemic stroke. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 118(3-2), 61-68. PubMed

Manchenko, D.M., Glazova, N.Y., Levitskaya, N.G., Andreeva, L.A., Kamenskii, A.A., & Myasoedov, N.F. (2012). Semax, a synthetic ACTH(4-7) analog, induces long-term cognitive and neurochemical effects in rat models. Bulletin of Experimental Biology and Medicine, 152(6), 701-704. PubMed

Lebedeva, I.S., Panikratova, Y.R., Sokolov, O.Y., Kupriyanov, D.A., Kost, N.V., Molchanova, L.V., Myasoedov, N.F., & Rumshiskaya, A.D. (2018). Effects of Semax on the default mode network of the brain. Bulletin of Experimental Biology and Medicine, 165(5), 653-656. PubMed

Kolomin, T., Shadrina, M., Slominsky, P., Limborska, S., & Myasoedov, N. (2013). A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neuroscience & Medicine, 4, 223-252.

Storozhevykh, T.P., Tukhbatova, G.R., Senilova, Y.E., Pinelis, V.G., Andreeva, L.A., & Myasoyedov, N.F. (2007). 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, 143(5), 601-604. PubMed

Sciacca, M.F.M., Romanucci, V., Zarrelli, A., Monaco, I., Lolicato, F., Spinella, N., Galati, C., Grasso, G., La Rosa, C., Forni, M., Bhatt, D., Bhatt, D.K., Bhatt, S.M., Milardi, D., & Di Fabio, G. (2022). Semax, a synthetic regulatory peptide, affects copper-induced Abeta aggregation and amyloid formation in artificial membrane models. ACS Chemical Neuroscience, 13(3), 358-369. PubMed

Shevchenko, K.V., Nagaev, I.Y., Alfeeva, L.Y., Andreeva, L.A., Kamenskii, A.A., Shevchenko, V.P., Grivennikov, I.A., & Myasoedov, N.F. (2006). Kinetics of semax penetration into the brain and blood of rats after its intranasal administration. Russian Journal of Bioorganic Chemistry, 32(1), 57-62. PubMed

All references open in new window. These citations are provided for educational and research purposes only. This information is not intended to diagnose, treat, cure, or prevent any disease. Semax is intended for laboratory research use only.