Scientifically reviewed by
Dr. Ky H. Le, MD
The information presented in this article is for educational and research purposes only, intended for laboratory professionals, researchers and collaborators. This content does not constitute medical or clinical advice.
Most ACTH-derived peptides carry strong hormonal activity. Semax was engineered specifically to strip that away.
Developed at the Russian Academy of Sciences in the 1980s, Semax isolates the neurotrophic effects of adrenocorticotropic hormone (ACTH) while leaving its cortisol-stimulating activity behind. That design decision — a deliberate structural separation — made it one of the most studied synthetic neuropeptides in preclinical neuroscience.
This article covers what Semax is, how it’s structured, what preclinical research shows about its activity, and where in vitro investigation is currently focused.
Overview
- Semax is a synthetic heptapeptide analog of ACTH(4-10) with the sequence Met-Glu-His-Phe-Pro-Gly-Pro
- A C-terminal Pro-Gly-Pro tail gives Semax more resistance to peptidase breakdown than the ACTH(4-7) fragment alone
- Rat studies recorded a 1.4-fold rise in hippocampal BDNF protein, with TrkB phosphorylation, after Semax exposure
- Preclinical work points to three routes: BDNF signaling, gene expression changes and melanocortin receptor interactions
What is Semax Peptide?
Semax is a synthetic heptapeptide with the amino acid sequence Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP).
It is an analog of ACTH(4-10), the N-terminal fragment of adrenocorticotropic hormone. Unlike native ACTH, Semax produces no corticotropic activity — it does not stimulate cortisol secretion or interact with the adrenal axis in standard preclinical models.
Origins and structural design
ACTH’s capacity to influence cognition and neurological function has been documented since the 1950s. Researchers at the Russian Academy of Sciences spent decades attempting to isolate those neurotrophic properties from the hormonal effects.
Semax was the result. The ACTH(4-7) fragment — Met-Glu-His-Phe — was retained for its neurotrophic activity, while the hormonal sequence was excluded. The compound was first described in scientific literature in 1991 and has since been studied across a range of preclinical neurological models.
The role of the Pro-Gly-Pro tripeptide
The PGP (Pro-Gly-Pro) sequence at Semax’s C-terminus was added to address a stability problem.
The ACTH(4-7) fragment alone degrades rapidly in serum due to peptidase activity. Adding the PGP tripeptide confers resistance to enzymatic breakdown, extending the compound’s serum stability period in animal studies. Semax has a molecular weight of 813.92 Daltons and is classified as a melanocortin-related peptide.
Semax Mechanisms in Preclinical Research
Semax doesn’t appear to work through a single pathway. Preclinical research has identified at least three distinct mechanistic routes — BDNF modulation, genome-wide gene expression changes, and melanocortin receptor interactions — each investigated independently across multiple study designs.
BDNF and TrkB upregulation
The most consistently documented effect of Semax in preclinical models is its modulation of brain-derived neurotrophic factor (BDNF) and its signaling receptor, TrkB.
Dolotov et al. (2006) found that Semax exposure in rats produced a 1.4-fold increase in BDNF protein levels alongside a 3-fold increase in exon III BDNF mRNA in rat hippocampus, with accompanying TrkB phosphorylation. [1]
A related study from the same group in the Journal of Neurochemistry identified specific, calcium-dependent binding sites for Semax in rat basal forebrain tissue, with BDNF protein levels rising within 3 hours of exposure.[2]
These findings suggest Semax interacts with specific binding sites in the basal forebrain — which may at least partly account for the BDNF changes observed downstream.
Genome-wide gene expression modulation
A 2014 genome-wide transcriptomics study in BMC Genomics by Medvedeva et al. examined Semax’s effect on rat brain cortex following permanent middle cerebral artery occlusion (pMCAO). Semax modulated immune-response gene expression, particularly genes encoding chemokines and immunoglobulins, at both 3h and 24h post-occlusion. Twenty-four genes related to vascular function (endothelial migration, smooth muscle cell activity, vasculogenesis) also showed altered expression.[3]
More recently, Filippenkov et al. (2024) used RNA-Seq to show that Semax shifted gene expression profiles in rat frontal cortex at 24 hours after transient MCAO, changing expression of 1,171 genes associated with immune and neurosignaling pathways.[4]
Melanocortin receptor interactions
Semax interacts with melanocortin receptors, though the precise pharmacology is still being characterized.
Available in vitro and in vivo data indicate Semax acts as a competitive antagonist or partial agonist at MC4 and MC5 receptors, without apparent interaction at MC3. Semax has also been shown to inhibit enkephalinase enzymes — proteins responsible for the degradation of endogenous regulatory peptides — at IC50 concentrations around 10 μM. This property is shared with Selank, a structurally related research peptide. For a side-by-side comparison of these compounds, see our Selank vs. Semax research overview.
Semax in Preclinical Research Models
Researchers have applied Semax across several distinct preclinical model categories, each probing different aspects of its mechanistic profile.
Cerebral ischemia models
A 2009 study by Dmitrieva et al. published in Cellular and Molecular Neurobiology examined neurotrophin mRNA expression in rat cortex following pMCAO. Semax activated transcription of BDNF, TrkC, and TrkA at 3h post-occlusion, and NGF at 24h — selectively in ischemic tissue rather than sham-operated controls.[5]
At the protein level, Sudarkina et al. (2021) used immunodetection in a transient MCAO model to show that Semax exposure was associated with upregulation of CREB and downregulation of MMP-9, c-Fos, and JNK in both ipsilateral cortex and subcortical structures at 24h.[6]
Chronic stress models
Inozemtseva et al. (2024) published in the European Journal of Pharmacology examined Semax in a chronic unpredictable stress (CUS) model using male Sprague-Dawley rats. In this model, Semax exposure was associated with changes in anhedonia-related behavior, body weight, adrenal size and hippocampal BDNF levels. The authors proposed that Semax’s activity at ACTH(4-10) receptors and the melanocortin system may modulate HPA axis regulation in stress conditions.[7]
Optic nerve and neuronal research
Semax has also been explored in optic nerve and neuronal research models, an area that overlaps with our coverage of peptides for ocular and retinal research. The peptide’s documented BDNF-elevating activity has made it a subject of interest in models where neurotrophin support is mechanistically relevant.
Preclinical research applications
| Research Area | Model Type | Observed Activity |
|---|---|---|
| BDNF/TrkB signaling | Rat hippocampus, basal forebrain | BDNF protein and mRNA upregulation |
| Neurotrophin gene expression | Rat ischemic cortex (pMCAO) | Activation of BDNF, NGF, TrkA, TrkC mRNA |
| Immune gene modulation | Rat brain cortex (focal ischemia) | Chemokine and immunoglobulin gene expression changes |
| Vascular gene expression | Rat brain (pMCAO) | Altered endothelial and smooth muscle gene profiles |
| Melanocortin receptor activity | In vitro and in vivo rat models | MC4/MC5 competitive interaction |
| Enkephalinase inhibition | In vitro | Degradation inhibition of endogenous regulatory peptides |
| Stress models | | Rat CUS model | | HPA axis and BDNF marker changes |
| Cerebral ischemia-reperfusion | Rat tMCAO | CREB upregulation, MMP-9/JNK downregulation |
All applications are preclinical or in vitro. Semax supplied by BioLongevity Labs is for research use only.
How Semax compares to Selank
Semax shares some structural and pharmacological territory with Selank, another ACTH-related synthetic peptide.
Both are derived from the ACTH melanocortin peptide family, both inhibit enkephalinase enzymes, and both have been studied across CNS-related preclinical models. The main difference is mechanistic emphasis. Selank research has focused more on immunomodulatory and GABAergic pathways, while Semax research has focused on BDNF signaling in ischemia models.
Sourcing Semax for in vitro research
Researchers requiring Semax for laboratory use need a supplier that documents what they’re shipping.
BioLongevity Labs provides research-grade Semax with independent third-party analytical testing. Each batch is checked by HPLC purity analysis and LC-MS molecular verification, with COA documentation available online prior to purchase.
All BioLongevity Labs peptides are manufactured in the USA, with complete analytical documentation available online.
Semax from BioLongevity Labs is supplied strictly for research use.
Scientific Reviewer
This research article has been scientifically reviewed and fact-checked by Dr. Ky H. Le, MD. Dr. Le earned his medical degree from St. George’s University School of Medicine and completed his residency training at Memorial Hermann Southwest Hospital. Board-certified in family medicine with experience in hospital medicine, he brings over two decades of clinical experience to reviewing research content and ensuring scientific accuracy.
About BioLongevity Labs
BioLongevity Labs supplies USA-made research peptides for in vitro laboratory applications. All compounds undergo independent third-party testing to verify purity and composition, with full certificates of analysis available for researchers requiring documentation. Browse our complete peptide catalog to find research-grade peptides for your laboratory needs.
References
- Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, et al. Semax, an analog of ACTH(4–10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Elsevier BV; 2006. https://doi.org/10.1016/j.brainres.2006.07.108
- Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, et al. Semax, an analogue of adrenocorticotropin (4–10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. Wiley; 2006. https://doi.org/10.1111/j.1471-4159.2006.03658.x
- Medvedeva EV, Dmitrieva VG, Povarova OV, Limborska SA, Skvortsova VI, Myasoedov NF, 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. Springer Science and Business Media LLC; 2014. https://doi.org/10.1186/1471-2164-15-228
- Filippenkov IB, Shpetko YYu, Stavchansky VV, Denisova AE, Gubsky LV, Andreeva LA, et al. ACTH-like peptides compensate rat brain gene expression profile disrupted by ischemia a day after experimental stroke. MDPI AG; 2024. https://doi.org/10.3390/biomedicines12122830
- Dmitrieva VG, Povarova OV, Skvortsova VI, Limborska SA, Myasoedov NF, Dergunova LV. Semax and Pro-Gly-Pro activate the transcription of neurotrophins and their receptor genes after cerebral ischemia. Springer Science and Business Media LLC; 2009. https://doi.org/10.1007/s10571-009-9432-0
- Sudarkina OYu, Filippenkov IB, Stavchansky VV, Denisova AE, Yuzhakov VV, Sevan’kaeva LE, et al. Brain protein expression profile confirms the protective effect of the ACTH(4–7)PGP peptide (Semax) in a rat model of cerebral ischemia-reperfusion. MDPI AG; 2021. https://doi.org/10.3390/ijms22126179
- Inozemtseva LS, Yatsenko KA, Glazova NY, Kamensky AA, Myasoedov NF, Levitskaya NG, et al. Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress. Elsevier BV; 2024. https://doi.org/10.1016/j.ejphar.2024.177068
