How Does Semax Work?

What semax is

Semax is written in the literature as ACTH(4-7)-Pro-Gly-Pro. It combines a short fragment of adrenocorticotropic hormone (ACTH) with a C-terminal Pro-Gly-Pro (PGP) tripeptide. Papers group it with the noncorticotropic synthetic analogs of the ACTH(4-10) fragment, meaning peptides derived from ACTH that are not described as acting on the adrenal cortex the way ACTH itself does.Animal study · PMID 39442746Animal study · PMID 19633950

Several groups describe semax as a heptapeptide analog of the N-terminal ACTH(4-10) fragment. The same papers place it among peptides that can affect the production and activity of neurotrophins, the family of proteins that regulate survival, differentiation and maintenance of different neuron populations. That framing explains why most semax research measures neurotrophin genes rather than hormone levels.Animal study · PMID 19662538Animal study · PMID 17353092

Neurotrophin genes in the normal rat brain

A 2007 study in male Wistar rats measured neurotrophin gene expression by real-time PCR 1 hour after semax exposure. Expression of both Bdnf and Ngf rose in the hippocampus. Bdnf expression also rose in the brainstem and cerebellum, while Ngf expression fell in the frontal cortex. The authors summarised the result as rapid, gene-specific and region-specific changes in neurotrophin expression in the normal rat brain.Animal study · PMID 17353092

A 2010 study followed the time course in more detail, sampling at 20 min, 40 min, 90 min, 3 h, 8 h and 24 h. The changes ran in different directions by region. At 20 minutes, expression of both genes was lower in the hippocampus and retina and higher in the frontal cortex. In the retina, Ngf stayed practically constant at first, while Bdnf was significantly higher at 90 minutes.Animal study · PMID 19662538

The 2007 study used a single time point and asked a narrow question: whether neurotrophin genes respond in the intact brain, outside any injury model. Earlier work cited in that paper had linked semax to neurotrophin gene expression in neuron and glial cell cultures; the in vivo study tested whether the same genes moved in living tissue, and found that they did, in a pattern that differed by region.Animal study · PMID 17353092

These two studies show why a one-line summary of semax and BDNF is too simple. The direction of change depended on the gene, the tissue and the time point, and both studies measured mRNA in healthy animals without testing any functional endpoint.Animal study · PMID 17353092Animal study · PMID 19662538

Neurotrophins and their receptors after experimental ischemia

In a rat model of permanent middle cerebral artery occlusion, a 2010 study analysed cortex at three time points. Under semax, transcription of Bdnf, TrkC and TrkA was higher at 3 h after occlusion, Nt-3 and Ngf at 24 h, and Ngf at 72 h. Under the PGP tripeptide alone, transcription of Bdnf and TrkC was higher at 3 h, and Ngf, TrkB, TrkC and TrkA at 24 h.Animal study · PMID 19633950

The same study compared rats without surgery, sham-operated rats and rats with occlusion. Semax selectively affected transcription of neurotrophins and their receptors in the ischemic cortex, whereas the influence of PGP alone was mainly unspecific. That contrast is one of the few direct tests of whether the ACTH fragment adds anything beyond the tripeptide.Animal study · PMID 19633950

A 2011 study used a different model, bilateral common carotid artery occlusion, and sampled frontal lobes, hippocampus and cerebellum from 30 minutes to 24 h. Ischemia lowered gene expression in the hippocampus. Semax and PGP acted mainly in the frontal cortex and hippocampus. In the frontal cortex, semax lowered receptor mRNA while PGP raised it. The largest effect of both peptides was recorded in the hippocampus at 12 h after occlusion.Animal study · PMID 22295573

Whole-transcriptome studies after stroke models

Later work moved from single genes to RNA sequencing. In the penumbra-associated frontal cortex of rats 24 h after transient middle cerebral artery occlusion, a 2024 study counted 3774 differentially expressed genes under ischemia, 1539 under semax and 2066 under a related peptide, ACTH(6-9)PGP. Both peptides reduced ischemia-related expression distortions for 1171 genes associated with immune and neurosignaling pathways.Animal study · PMID 39767736

The same group then examined the striatum, the region containing the ischemic focus, in the same animals. The peptides produced fewer differentially expressed genes there than in the frontal cortex. Both tended to move hundreds of ischemia-disturbed genes back toward the non-ischemic profile, but 152 genes showed an even more disturbed profile under ACTH(6-9)PGP. About a hundred genes overlapped between both peptides in both tissues, mostly linked to neuroactive ligand-receptor interaction.Animal study · PMID 40650034

The 2024 study also noted that the pattern of peptide action on the transcriptome depended on how much time had passed since occlusion, compared with an earlier 4.5 h time point. Timing, like brain region, is therefore part of any description of how semax works.Animal study · PMID 39767736

Behavior and stress measures in rats

A 2024 study tested semax and another ACTH(4-10) analog, Melanotan II, in male Sprague-Dawley rats under chronic unpredictable stress. Stress produced anhedonia in the sucrose preference test, suppressed body-weight gain, adrenal hypertrophy and hippocampal BDNF levels below those of unstressed rats. With either peptide, those changes were reversed or substantially attenuated. In the forced swim test, neither stress nor the peptides changed immobility time.Animal study · PMID 39442746

The authors of that study placed the work in the context of the hypothalamic-pituitary-adrenal axis, which regulates itself through feedback at several levels, including ACTH-mediated feedback. They tested the two peptides as noncorticotropic ACTH(4-10) analogs and reported the result as limited to male rats.Animal study · PMID 39442746

An earlier Russian-language study gave semax to white rats for 10 or 14 days and reported changes in measures of anxiety-like and depression-like behavior, with no change in exploratory activity in a non-stressful environment. The authors suggested a role for the serotonergic system and hippocampal BDNF, but the abstract presents these as possible explanations rather than measured mechanisms.Animal study · PMID 17850024

Limits of the semax evidence

Every study summarised here used rats, and most measured mRNA rather than protein or function. Several of the papers come from the same institutes and author groups, and two are indexed only with Russian-language full texts. One 2010 paper states that semax has effects on learning, memory formation and neuroprotection in rodents and humans, but none of the studies cited here tested people.Animal study · PMID 19662538Animal study · PMID 22295573Animal study · PMID 17850024

The receptor that semax acts on is also not settled by these abstracts. The 2024 stress study grouped semax with noncorticotropic melanocortins, but it measured behavior, adrenal weight and hippocampal BDNF, not receptor binding. The evidence describes what changes after semax exposure in rat tissue more clearly than it describes the first molecular step.Animal study · PMID 39442746

The studies at a glance

Key semax studies, all in rats. Results are as reported in each paper's abstract.

Frequently asked questions