Semax is a drug which is used mostly in Russia for a broad range of conditions but predominantly for its purported nootropic, neuroprotective, and neurorestorative properties. Semax has not been evaluated, approved for use, or marketed in most other countries. It is prescribed in eastern Europe and Russia for brain trauma.

Etymology

Semax is composed of seven amino acid residues: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), which is reflected in the name – from an abbreviation of “Seven amino acids”- in Russian: СЕМь АминоКиСлот – СЕМАКС.

Marketing

Marketing Development and production: PEPTOGEN (Russian Federation) Joint-Stock Company «Innovative Research-and-Production Center «Peptogen» (JSC «Peptogen»), Russian Federation was founded in 2005 with the participation of the Institute of Molecular Genetics of the Russian Academy of Sciences

Medical uses

Semax 1% from Russia

Semax has undergone extensive study in Russia and is on the Russian List of Vital & Essential Drugs approved by the Russian Federation government on December 7, 2011.^[1] Medical uses for Semax include treatment of stroke, transient ischemic attack, memory and cognitive disorders, peptic ulcers, optic nerve disease, and to boost the immune system.^[2][3][4][5]

Pharmacology

Pharmacodynamics

In animals, Semax rapidly elevates the levels and expression of brain-derived neurotrophic factor (BDNF) and its signaling receptor TrkB in the hippocampus,^[6] and rapidly activates serotonergic and dopaminergic brain systems.^[7][8] Accordingly, it has been found to produce antidepressant-like and anxiolytic-like effects,^[9][10] attenuate the behavioral effects of exposure to chronic stress,^[9][10] and potentiate the locomotor activity produced by D-amphetamine.^[8][11] As such, it has been suggested that Semax may be effective in the treatment of depression.^[12]

Though the exact mechanism of action of Semax is unclear, there is evidence that it may act through melanocortin receptors. Specifically, there is a report of Semax competitively antagonizing the action of the melanocortin receptor full agonist α-melanocyte-stimulating hormone (α-MSH) at the MC₄ and MC₅ receptors in both in vitro and in vivo experimental conditions, indicating that it may act as an antagonist or partial agonist of these receptors.^[13] Semax did not antagonize α-MSH at the MC₃ receptor, though this receptor could still be a target of the drug.^[13] As for the MC₁ and MC₂ receptors, they were not assayed.^[13] In addition to actions at receptors, Semax, as well as a related peptide drug, Selank, have been found to inhibit enzymes involved in the degradation of enkephalins and other endogenous regulatory peptides (IC₅₀ = 10 μM), though the clinical significance of this property is uncertain.^[14]

Pharmacokinetics

As a peptide, Semax has poor oral bioavailability and hence is administered parenterally as a nasal spray or subcutaneous injection.

Human trials

In a 2018 study involving 24 healthy participants, Semax was shown to increase fMRI default mode network activity relative to placebo.^[15]

In an earlier 1996 study, 250-1000 ug/kg of Semax improved attention and short term memory in 11 healthy subjects performing 8 hour work shifts, though the effects were most pronounced when subjects were fatigued (after the shift was over) and the effects lasted going into the next day.^[16] In a follow-up memory test administered the morning after Semax administration, the treatment group made more correct responses (71%) than the control group (41%).^[16]

A study involving 110 patients recovering from ischemic stroke reported increases in BDNF (correlated with early rehabilitation) in patients administered Semax.^[17]

As of November 2023, there are no published human trials involving Semax outside of Russia and Post-Soviet states.^[18]

Chemistry

Semax is a heptapeptide and synthetic analogue of a fragment of adrenocorticotropic hormone (ACTH), ACTH (4-10), of the following amino acid sequence: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP in single-letter form).

Abstract

Background

The nootropic neuroprotective peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has proved efficient in the therapy of brain stroke; however, the molecular mechanisms underlying its action remain obscure. Our genome-wide study was designed to investigate the response of the transcriptome of ischemized rat brain cortex tissues to the action of Semax in vivo.

Conclusions

Semax affects several biological processes involved in the function of various systems. The immune response is the process most markedly affected by the drug. Semax altered the expression of genes that modulate the amount and mobility of immune cells and enhanced the expression of genes that encode chemokines and immunoglobulins. In conditions of rat brain focal ischemia, Semax influenced the expression of genes that promote the formation and functioning of the vascular system.

The immunomodulating effect of the peptide discovered in our research and its impact on the vascular system during ischemia are likely to be the key mechanisms underlying the neuroprotective effects of the peptide.

Keywords: Semax, Pro-Gly-Pro, Focal cerebral ischemia, Expression Beadchip gene array, Gene expression, Immune cells, Immunoglobulins

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Background

Ischemic brain stroke is one of the major contributors to mortality and disability worldwide. As the result of a critical reduction of blood flow in the brain, it causes massive loss of neurons and leads to the formation of the necrotic core and the penumbra zone [1].

One of the drugs that is effectively employed currently in cerebral stroke therapy is the Semax (Met-Glu-His-Phe-Pro-Gly-Pro), which is a synthetic peptide consisting of a fragment of ACTH(4–7) and the C-terminal tripeptide Pro-Gly-Pro (PGP). Studies have shown that Semax promotes the survival of neurons during hypoxia [2] and glutamate neurotoxicity [3]. It also shows neuroprotective properties and contributes to mitochondrial stability under stress induced by the deregulation of calcium ion flow [3]. The action of Semax causes the inhibition of nitric oxide synthesis [4], improves the trophic supply of the brain [5], and protects the nervous system effectively against diseases of the optic nerve [6]. This peptide also possesses nootropic activity [7].

However, the molecular mechanisms underlying the action of Semax remain unclear. We have previously shown the effect of Semax on the expression of genes that encode neurotrophic factors and their receptors in an experimental model ischemia in the rat brain [8,9].

This genome-wide study was performed to elucidate the transcriptome response of the ischemized focal tissues of the rat brain to the action of Semax in vivo. The main task of our study was to identify genes with an altered expression that accounts for the positive effect exerted by Semax in the treatment of patients with ischemic stroke [10,11].