The Neuroprotective and Gastroprotective Potential of Semax

Semax is a synthetic heptapeptide (Met–Glu–His–Phe–Pro–Gly–Pro) originally derived from fragments of adrenocorticotropic hormone (ACTH) but lacking hormonal activity. It consists of a 4-amino acid fragment (Met-Glu-His-Phe), which is a common part in the sequence of all melanocortin hormones, such as ACTH, and a Pro-Gly-Pro fragment as a stabilizer, which is attached at the C-terminus.

Data collected from laboratory research has repeatedly linked this peptide to changes in neurotrophin dynamics, especially brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are considered key regulators of neuronal survival, differentiation, and plasticity. Synthetic peptides like Semax that may support neurotrophin synthesis are of particular research interest. This is in part because these appear to be tightly linked to synaptic remodeling and long-term adaptive processes.

 

Research

Semax Interactions with Neutrophin Synthesis

Cellular experiments performed by Shadrina et al., as well as previous researchers, suggest that Semax may modulate neurotrophin gene expression in primary glial cell cultures collected from murine models.⁽¹⁾ Glial cells are the supportive cells of the central nervous system, providing metabolic support, regulating the extracellular environment, and releasing signaling molecules that support neuronal survival and plasticity. When cultures were exposed to Semax, the researchers commented that “BDNF mRNA level was increased eight-fold in comparison with control, and NGF mRNA level was increased five-fold” approximately after 30 minutes following the exposure. This rapid upregulation observed in these murine models was followed by a decline over the next few hours, and then by a smaller secondary increase at later time points.

In control conditions, such changes were not observed, apart from modest fluctuations associated with serum supplementation. These results suggest that Semax is capable of inducing transient yet pronounced increases in neurotrophin gene expression in glial cells.

Further research by Shadrina et al. suggested the peptide may increase BDNF and NGF levels in the frontal cortex and retinal neurons about two-fold within 90 minutes, with a peak by 90 minutes.⁽²⁾ The researchers also suggest that after 24 hours of experimentation, expression had generally returned closer to control values. These observations suggest that Semax may induce both rapid and delayed transcriptional responses, with an early divergence between tissues followed by a convergent late-phase upregulation.

Kinetics of this type may imply activation of immediate intracellular signaling cascades—possibly involving CREB or MAPK pathways—followed by autoregulatory feedback that shapes the sustained transcriptional profile. The simultaneous regulation of both NGF and BDNF points to a broader modulatory role for Semax across the neurotrophin family, rather than a selective interaction with a single gene. Further research by Dolotov et al. suggests that these implications may be region-specific.⁽³⁾ The combination of selective binding and selective BDNF induction points to a model in which Semax acts directly at basal forebrain cell membranes to modulate neurotrophin production, particularly in mammalian glial cells such as astrocytes. Because cholinergic neurons of this region are strongly better-supported by BDNF, the transient upregulation may contribute to plasticity-related processes in connected areas such as the cortex and hippocampal nerve cells.

Semax Interactions with Neutrophin Signaling and Neuroplasticity

Additional laboratory assays by Dolotov et al. indicate that Semax may support not only BDNF synthesis, but also apparently exert a notable interaction with the BDNF receptor system itself – specifically the trkB (Tropomyosin receptor kinase B) receptors.⁽³⁾ In hippocampal nerve cell culture preparations, Semax implication apparently supports tyrosine phosphorylation of trkB receptors, which is considered essential for activating the canonical PI3K–Akt and MAPK cascades. The researchers observed that there was an apparent “1.6-fold increase of trkB tyrosine phosphorylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively.” These pathways govern survival signaling, synaptic consolidation, and plasticity, suggesting that the peptide facilitates a more responsive receptor state.

Supporting this, an increase in trkB mRNA expression was detected 24 hours after exposure, pointing to longer-term adjustments in receptor availability. While changes in BDNF protein were also observed, the receptor data imply that Semax may act not only by modulating ligand supply but by tuning the sensitivity and signaling capacity of trkB itself. This dual action—supporting receptor phosphorylation acutely and adjusting receptor expression over time—frames Semax as a modulator of neurotrophin signaling dynamics at the receptor level.

Research by Gusev et al. also suggests that Semax-driven BDNF signaling should translate into more robust neurite outgrowth and branching, denser and more mature synapses, better-supported axonal sprouting after injury-like assays, and faster recovery of network dynamics after metabolic or excitotoxic stress.⁽⁵⁾ These actions are expected to be most clear in data collected from studies of neuron–astrocyte systems, where astroglia contribute substantially to the BDNF supply and shape the extracellular milieu for trkB signaling. Mechanistically, Semax appears to operate through both BDNF-mediated and BDNF-adjacent routes. Alongside direct up-regulation of BDNF and trkB activity, Semax has been linked to increases in cAMP/CREB signaling and to modulation of cholinergic tone—processes that cooperate with neurotrophin pathways to stabilize synapses and promote structural remodeling.

Semax Interactions with the Default Mode Network

An fMRI investigation by Lebedeva et al. examined how Semax may support the spontaneous network activity in brain tissues, with a focus on the default mode network (DMN).⁽⁶⁾ Within 20 minutes of experimentation, the researchers observed an apparent marked expansion of the frontal DMN subcomponent, particularly in regions including the paracingular gyrus, frontal cingulate cortex, and frontal pole. This contrasted with the placebo condition, where small initial increases were followed by a decline in DMN volume at the same time point. The enlargement of the DMN cluster under Semax exposure may reflect stronger synchronization of neuronal populations or localized changes in hemodynamic parameters captured through BOLD signals. Given that the DMN integrates high-order associative cortical areas, these findings indicate that Semax may alter large-scale network dynamics and functional connectivity patterns in a time-dependent manner.

Further experimentation by Kaplan et al. suggests that experimentation with Semax has been observed to cause a suppression of delta rhythms accompanied by an increase in alpha and low beta activity.⁽⁷⁾ Such a profile is often interpreted in pharmacoelectroencephalography as reflecting better-supported vigilance and better-supported cognitive integration, resembling that of nootropic compounds.

Additional evaluation under conditions of transient metabolic challenge using a hyperventilation model to induce ischemia-like shifts in cortical oscillations in laboratory settings suggested that Semax may markedly attenuate the usual EEG changes. In control conditions, hyperventilation produced strong increases in slow-wave activity (delta, theta) and reductions in alpha power. Pre-exposure with Semax significantly blunted these alterations, in some cases nearly eliminating them, suggesting that the peptide may exert stabilizing support for cortical excitability during hypoxic stress.

Semax Regenerative Potential in Other Cell Cultures

Apart from the potential of the peptide on nerve cells and BDNF signaling, some studies have suggested that Semax may exert protective actions against gastric lesions produced by stress, ethanol, and acids. For example, the team of Zhuikova et al. investigated this line of research by examining whether Semax may modulate ulceration induced by the agent indomethacin.⁽⁸⁾ In this model, indomethacin produced marked damage to the gastric mucosa, accompanied by hemorrhagic lesions and a significant reduction in regional blood supply.

Semax exposure shortly after indomethacin may have contributed to reducing the ulcerated area by approximately 70% relative to control conditions. To clarify the mechanism, gastric microcirculation was measured directly using the hydrogen clearance method. Indomethacin led to a progressive reduction in blood supply—approximately 20% within the first 20 minutes and up to 40% by 40 minutes after evaluation, with suppression persisting throughout the recording period.

In these studies, Semax alone did not alter baseline gastric circulation; however, when exposure was right after indomethacin, it significantly attenuated the decline in perfusion. These findings suggest that the protective potential of Semax in this model is linked to its ability to preserve or restore blood supply. Independent observations have also been made for anticoagulant, fibrinolytic, and anti-aggregatory activities of the peptide, which may contribute to its relevance to mucosal circulation.

Further research by Ivanikov et al. has posited that Semax may also reduce mucosal damage caused by ethanol, stress, or other agents. It accelerated the recovery of gastric and pancreatic cellular structure following injury by agents like these.⁽⁹⁾ Once again, the suggested mechanism is related to a potential support on blood rheology, exhibiting anticoagulant and fibrinolytic activities while reducing platelet aggregation. The peptide has also been suggested to decrease vascular permeability and support microcirculation in mammalian research models whose pancreatic cells show signs of injury or disease.

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Shadrina MI, Dolotov OV, Grivennikov IA, Slominsky PA, Andreeva LA, Inozemtseva LS, Limborska SA, Myasoedov NF. Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analog. Neurosci Lett. 2001 Aug 3;308(2):115-8. doi: 10.1016/s0304-3940(01)01994-2. PMID: 11457573.
2. Shadrina M, Kolomin T, Agapova T, Agniullin Y, Shram S, Slominsky P, Lymborska S, Myasoedov N. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. J Mol Neurosci. 2010 May;41(1):30-5. doi: 10.1007/s12031-009-9270-z. Epub 2009 Aug 7. PMID: 19662538.
3. Dolotov OV, Karpenko EA, Seredenina TS, Inozemtseva LS, Levitskaya NG, Zolotarev YA, Kamensky AA, Grivennikov IA, Engele J, Myasoedov NF. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. J Neurochem. 2006 Apr;97 Suppl 1:82-6. doi: 10.1111/j.1471-4159.2006.03658.x. PMID: 16635254.
4. Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, Dubynina EV, Novosadova EV, Andreeva LA, Alfeeva LY, Kamensky AA, Grivennikov IA, Myasoedov NF, Engele J. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006 Oct 30;1117(1):54-60. doi: 10.1016/j.brainres.2006.07.108. Epub 2006 Sep 22. PMID: 16996037.
5. Gusev EI, Martynov MY, Kostenko EV, Petrova LV, Bobyreva SN. Éffektivnost’ semaksa pri lechenii bol’nykh na raznykh stadiiakh ishemicheskogo insul’ta [The efficacy of semax in the treatment of patients at different stages of ischemic stroke]. Zh Nevrol Psikhiatr Im S S Korsakova. 2018;118(3. Vyp. 2):61-68. Russian. doi: 10.17116/jnevro20181183261-68. PMID: 29798983.
6. Lebedeva IS, Panikratova YR, Sokolov OY, Kupriyanov DA, Rumshiskaya AD, Kost NV, Myasoedov NF. Effects of Semax on the Default Mode Network of the Brain. Bull Exp Biol Med. 2018 Sep;165(5):653-656. doi: 10.1007/s10517-018-4234-3. Epub 2018 Sep 17. PMID: 30225715.
7. Kaplan AY, Kochetova AG, Nezavibathko VN, Rjasina TV, Ashmarin IP. Synthetic acth analogue semax displays nootropic‐like activity in humans. Neuroscience Research Communications. 1996 Sep;19(2):115-23.
8. Zhuikova SE, Sergeev VI, Samonina GE, Myasoedov NF. Possible mechanism underlying the effect of Semax on the formation of indomethacin-induced ulcers in rats. Bull Exp Biol Med. 2002 Jun;133(6):577-9. doi: 10.1023/a:1020285909696. PMID: 12447470.
9. Ivanikov IO, Brekhova ME, Samonina GE, Myasoedov NF, Ashmarin IP. Therapy of peptic ulcer with semax peptide. Bull Exp Biol Med. 2002 Jul;134(1):73-4. PMID: 12459874. https://doi.org/10.1023/a:1020621124776