Mechanism of action
Semax is the ACTH(4-7) fragment Met-Glu-His-Phe extended at the C-terminus by Pro-Gly-Pro, a modification the literature describes as increasing resistance to enzymatic degradation. Unlike the parent hormone it is reported to be largely devoid of corticotropic activity, and it lacks the Arg-Trp motif of the melanocortin pharmacophore, so an action mediated by melanocortin receptors is not established. Radioligand work on rat basal forebrain membranes instead identified specific, reversible and calcium-dependent binding sites of nanomolar affinity that were not assigned to any cloned receptor (Dolotov et al., J Neurochem 2006). The best-characterised downstream signal is neurotrophin signalling: in rat hippocampus and basal forebrain, intranasally applied Semax raised BDNF protein levels and altered trkB expression. Rodent studies additionally describe modulation of monoaminergic and cholinergic transmission and of inflammation- and vasculature-related gene expression in focal ischemia models.
State of evidence
The evidence on Semax is regionally asymmetric. The mechanistic basis is preclinical: cell-culture and rodent studies on binding sites, BDNF and trkB expression, and neuroprotection after experimental focal cortical ischemia (Dolotov et al. 2006; Romanova et al. 2006). Clinical data come almost entirely from Russia, where Semax is registered as a medicinal product and used in neurological practice, chiefly in acute ischemic stroke and cognitive indications. Russian-language reports include work on acute stroke (Miasoedova et al. 1999) and a rehabilitation study in 110 patients that reported higher plasma BDNF levels and larger Barthel index gains in the Semax subgroups (Gusev et al. 2018); blinding and placebo control are not reported there. No marketing authorisation exists from the EMA or the FDA, and no large, independent, randomised double-blind trial in an international peer-reviewed journal is available. Blinding, reporting quality and independent replication are the central gaps; efficacy and safety are therefore not established.
Storage and handling
General handling rules for lyophilized peptides apply: store cool, dry and protected from light. After reconstitution, peptide solutions are kept refrigerated in laboratory practice and used within a few days; repeated freeze-thaw cycles are generally avoided.
Questions about the research
- What is Semax investigated for in research?
- Semax is investigated mainly in research on cognition, learning and memory, and on neuroprotection after cerebral ischemia. The central question is whether the peptide influences neurotrophin signalling, in particular BDNF and its receptor trkB. A further strand examines the expression of inflammation- and vasculature-related genes in stroke models.
- What is the state of the evidence on Semax?
- The mechanistic data come from cell culture and rodent models, the clinical data almost entirely from Russia, where Semax is registered as a medicinal product. Those clinical reports are mostly published in Russian and generally do not report blinding or placebo control. Large, independent, randomised double-blind trials are lacking, as is any approval by the EMA or the FDA. Efficacy and safety are therefore not established.
Sources
- Filippenkov et al., Genes 2023 (immune gene expression in rat brain)DOI: 10.3390/genes14071382PMID: 37510287
- Dolotov et al., Brain Res 2006DOI: 10.1016/j.brainres.2006.07.108PMID: 16996037
- Dolotov et al., J Neurochem 2006DOI: 10.1111/j.1471-4159.2006.03658.xPMID: 16635254
- Romanova et al., Bull Exp Biol Med 2006DOI: 10.1007/s10517-006-0445-0PMID: 17603664
- Miasoedova et al., Zh Nevrol Psikhiatr Im S S Korsakova 1999PMID: 10358912
- Gusev et al., Zh Nevrol Psikhiatr Im S S Korsakova 2018DOI: 10.17116/jnevro20181183261-68PMID: 29798983