Semax

Semax is a seven-amino-acid peptide based on the 4-10 fragment of adrenocorticotropic hormone (ACTH). It is given as a nasal spray. In rodents and humans it affects learning and memory, and it has marked neuroprotective effects [1]. It is described as used in acute stroke therapy [2].

A note on the evidence. Semax's clinical literature is almost entirely in Russian journals. Those papers are read here in the original rather than through their English abstracts, which routinely omit the dose and the route; a paper is left out only when neither an abstract nor a full text can be obtained at all. Russian-language references are marked in the reference list.

In a 1997 study, 30 patients in the acute phase of ischemic stroke received Semax alongside standard treatment and were compared with 80 patients on standard treatment alone. Semax sped the recovery of neurological, especially motor, function [4]. A 2018 study found Semax raised blood BDNF and, especially with early rehabilitation, sped functional recovery and improved motor performance on the Barthel index [5]. Neither abstract describes a randomized, placebo-controlled design.

Two small imaging studies have looked at what a single dose does to a healthy brain. In 52 volunteers, Semax and Selank each changed resting-state connectivity between the right amygdala and a region of right fusiform, inferior and middle temporal and parahippocampal cortex, measured 5 and 20 minutes after dosing and compared with placebo [6]. In 24 volunteers with a mean age of 44, 14 given 1% intranasal Semax and 10 placebo, the rostral, medial frontal part of the default mode network covered a larger volume in the Semax group [7]. Both are descriptive: neither links the change to a cognitive measure.

A binding site. Tritium-labeled Semax bound membranes from rat basal forebrain in a way that was time-dependent, specific and reversible, required calcium, and had a dissociation constant of 2.4 ± 1.0 nM with a Bmax of 33.5 ± 7.9 fmol/mg protein. The receptor itself has not been identified [1].

BDNF and trkB. Intranasal Semax at 50 or 250 µg/kg raised BDNF protein in the basal forebrain within three hours but not in the cerebellum, so the effect is regional rather than general [1]. In the hippocampus, a single 50 µg/kg dose raised BDNF protein 1.4-fold, tyrosine phosphorylation of its receptor trkB 1.6-fold, exon III BDNF mRNA 3-fold and trkB mRNA 2-fold; the same animals made more conditioned avoidance responses [3].

After experimental stroke. Rats had the middle cerebral artery permanently occluded and were given 100 µg/kg intraperitoneally at 15 minutes and 1, 4 and 8 hours. Semax raised cortical transcription of Bdnf, TrkC and TrkA at 3 hours, Nt-3 and Ngf at 24 hours and Ngf at 72 hours. The study's useful control is its comparison with Pro-Gly-Pro, the peptide's own C-terminal tripeptide, given alone: PGP produced a partly overlapping pattern, but it changed transcription in unoperated and sham-operated rats as well, whereas Semax acted selectively on the ischemic cortex [2].

Genome-wide. The same model, read on a 22,226-gene array, found 96 genes with altered expression at 3 hours and 68 at 24 hours, of which 51 were up. Only 10 genes appeared at both time points, and those reversed direction, so the early and late responses are different programs rather than one sustained one. At 24 hours, more than half of the affected genes were immune genes, mostly immunoglobulins and chemokines. Vascular genes - endothelial development and migration, smooth muscle cell migration, hematopoiesis, vasculogenesis - accounted for 24 changes at 3 hours and 12 at 24 hours. The authors read immunomodulation and the vascular response, rather than a direct action on neurons, as the likely basis of the neuroprotection [8].

Peptidase inhibition. In human serum, Semax inhibited enkephalin-degrading enzymes with an IC50 of 10 µM, far below puromycin's 10 mM. Its pentapeptide fragments were also active while the tri-, tetra- and hexapeptide fragments were not. Because those enzymes degrade other regulatory peptides too, this may prolong the action of endogenous peptides rather than represent an effect of Semax itself [9].

The cited abstracts do not report adverse events in detail, and no long-term safety study is indexed in English. The human studies are small. The peptide is rapidly broken down in the body [10].