A neuroactive peptide studied in the context of BDNF, cerebral ischemia, neural plasticity, and the inflammatory response
Overview
Semax is a short synthetic peptide of seven amino acids. Its sequence is Met-Glu-His-Phe-Pro-Gly-Pro, and it is described in the literature as a derivative of ACTH(4-10) or ACTH(4-7) with an added Pro-Gly-Pro, intended to improve biological stability relative to shorter ACTH segments [1,2]. Despite its structural origin in the ACTH pathway, Semax is not full ACTH and is not presented in the literature as a classic hormonal peptide of the stress axis. The main research interest in it relates to the nervous system: neurotrophic factors, the response to ischemic injury, gene expression, neuroinflammation, and synaptic plasticity [1-6]. The literature on Semax includes many preclinical studies and clinical publications, mainly from Russia, some of them relatively old. There is therefore an interesting biological foundation, but also methodological and geographical limitations relative to the standards of modern multicenter trials [5,7].
Biological Mechanism
One of the central axes around Semax is BDNF-TrkB. BDNF is a neurotrophic factor involved in neuron survival, synaptic plasticity, learning, and memory. TrkB is the main receptor through which BDNF exerts some of its effects. A study in rats found that Semax affected BDNF levels and TrkB expression in the hippocampus [1]. Another study found that Semax bound specifically and reversibly to cell membranes in the basal forebrain region in rats and raised BDNF levels in this region after experimental exposure [2]. The basal forebrain is a region associated with cholinergic systems, attention, and learning, so the finding drew interest in cognitive contexts. Beyond BDNF, Semax has also been studied in the context of the immune and inflammatory response after cerebral injury. Gene-expression studies in models of cerebral ischemia showed that Semax alters the expression of genes related to the immune system, blood vessels, cytokines, and stress responses [3,4].
Research Evidence
In models of cerebral ischemia, Semax showed neuroprotective effects in several animal studies. A 2014 genome-wide transcriptional analysis study found that Semax affected gene expression in the rat brain after focal ischemia, mainly in pathways related to the immune system and the vascular system [3]. Another study from 2017 suggested that some of the effects of Semax may operate through neuroimmune crosstalk, that is, communication between the nervous system and the immune system. The researchers found changes in the expression of genes for immune response, cytokines, and proteins related to cerebral injury [4]. In 2021 a proteomic study was published in a model of ischemia and reperfusion, which showed effects on proteins related to inflammation, cell death, and neural recovery [5]. In humans, there are clinical publications on Semax in the context of ischemic stroke. A 1997 clinical study examined Semax in the acute phase of hemispheric stroke, and another study from 2018 dealt with patients at various stages of ischemic stroke and with regard to BDNF and functional measures [6,7]. The studies are relevant, but should be interpreted with caution because of sample size, language, availability of details, and methodology compared with current standards.
BDNF, TrkB and Neural Plasticity
The relationship between Semax and BDNF is one of the most important axes in the literature. BDNF participates in synaptic plasticity, neuron survival, learning, and memory, while TrkB is one of the main receptors through which BDNF exerts its effects. Studies in rats found that Semax affected BDNF levels and TrkB expression in brain regions related to learning and neural function [1,2]. Nevertheless, it is important to interpret the BDNF findings with caution. An increase in BDNF in an animal model does not prove cognitive improvement in healthy humans. It does indicate neurotrophic potential and an ability of the peptide to affect the recovery environment of neurons. Semax is therefore especially suited to research on neural plasticity after stress, ischemia, or injury, and not only to popular discussion of "improving focus." The genomic studies of cerebral ischemia add an important layer. They show that Semax is related not only to BDNF, but also to immune and vascular pathways after cerebral injury [3,4]. After a stroke or experimental cerebral occlusion, tissue damage does not arise only from oxygen deprivation. There is an inflammatory response, infiltration of immune cells, damage to the blood-brain barrier, changes in the expression of chemokines and cytokines, and changes in glial cells. The effect of Semax on immune genes points to the possibility that it integrates into the broad response of the brain to injury. The clinical studies in Russian or from regional settings offer interesting data in ischemic stroke and neurological rehabilitation [6,7]. However, there are recognized limitations: some publications are old, samples are small, availability of full protocols is limited, and comparison with modern standards of late-phase trials is difficult. The evidence in humans is therefore not at the same level of strength as the animal and laboratory mechanism. It justifies research interest, but does not provide a global picture of efficacy, safety, and suitable populations.
Safety & Regulation
The safety data on Semax are not as extensive as for drugs that have undergone large global development programs. There are clinical reports of tolerability, but there is no large, long-term, multi-population database sufficient to assess rare risks or interactions with various neurological and psychiatric conditions. The FDA notes that compounded preparations containing Semax may raise concerns related to immunogenicity, aggregation, peptide-related impurities, and characterization of the active substance, and that the human safety data for proposed routes of exposure are limited or insufficient [8]. Therefore, from a research standpoint, Semax is an important peptide for understanding neurotrophins, neuroinflammation, and ischemia. From a clinical standpoint, the level of evidence is insufficient to draw broad conclusions about cognitive improvement or general treatment of neurological conditions.
Brain Penetration and Biological Breakdown
One of the topics that distinguishes Semax from many neural peptides is the interest in the intranasal route of administration studied in some of the publications. Preclinical studies suggest that the peptide or its metabolites can reach the nervous system, but also undergo relatively rapid degradation [1,2]. Such degradation is not necessarily a disadvantage, because short metabolites may be active, but it makes an unequivocal determination of mechanism difficult. When examining a possible effect on cognition, one should distinguish between three levels: an effect on neurotrophic factors, an effect on recovery after injury, and an effect on healthy people. The stronger evidence is found in the first two levels, especially in models of ischemia and in measures of BDNF, TrkB, and the neural immune response [1-5]. In contrast, broad claims about improved attention or memory in healthy people require larger, controlled, and more independent studies. In terms of safety as well, regional data or usage experience in a particular country do not replace broad regulatory evaluation. Questions such as interactions with psychiatric medications, effects in various neurological diseases, prolonged exposure, and uniform manufacturing remain important [8]. Semax is therefore an interesting neuroactive peptide, but the level of confidence varies greatly between the different research areas. A further point is the difference between acute neuroprotection and sustained cognitive improvement. A substance may reduce damage after ischemia in an animal model, but not necessarily improve learning in a healthy person. The findings on Semax should therefore be examined according to the clinical context in which they were tested, and not under one general heading of "nootropics."
Summary
Semax is a neuroactive peptide studied mainly in the BDNF-TrkB pathways, cerebral ischemia and neuroinflammatory response [1-5]. There are clinical publications limited in scope and methodology [6,7], and questions remain regarding effect size, long-term safety, formulation quality and reproducibility of the findings. The substance is intended for laboratory research use only.
Selected Research Sources
- Dolotov O.V. et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and TrkB expression in the rat hippocampus. Brain Research, 2006. DOI: 10.1016/j.brainres.2006.07.108. sciencedirect.com
- Dolotov O.V. et al. Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. Journal of Neurochemistry, 2006. PMID: 16635254
- Medvedeva E.V. et al. The peptide Semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia. BMC Genomics, 2014. PMID: 24661604
- Medvedeva E.V. et al. Semax regulates expression of immune response genes during ischemic brain injury in rats. Molecular Genetics and Genomics, 2017. PMID: 28255762
- Sudarkina O.Y. et al. Brain Protein Expression Profile Confirms the Protective Effect of Semax in a Rat Model of Cerebral Ischemia-Reperfusion. International Journal of Molecular Sciences, 2021. PMID: 34201112
- Gusev E.I. et al. Effectiveness of Semax in acute period of hemispheric ischemic stroke. Clinical and electrophysiological study, 1997. PMID: 11517472
- Gusev E.I. et al. The efficacy of Semax in the treatment of patients at different stages of ischemic stroke, 2018. PMID: 29798983
- U.S. Food and Drug Administration. Safety risks associated with certain bulk drug substances nominated for use in compounding. Entry for Semax. FDA.gov
