August 19, 2026 · 2 min read

Semax: an ACTH-derived heptapeptide and its BDNF and neuroprotection research

What the published rat studies report about Semax, a synthetic ACTH(4-10) analogue, including BDNF signaling in the hippocampus and gene expression after ischemia.

Semax is a heptapeptide with the sequence Met-Glu-His-Phe-Pro-Gly-Pro. It is built from a fragment of adrenocorticotropin (ACTH), the pituitary hormone, with a Pro-Gly-Pro tail added. It was developed and studied mainly by Russian research groups, and nearly all of the published work is in rodents.

The Semax sequence

Sequence: Methionine, Glutamic acid, Histidine, Phenylalanine, Proline, Glycine, Proline.

  • Hydrophobic
  • Negatively charged
  • Positively charged
  • Glycine or proline
Length
7 amino acids
Average mass
813.9 Da
Formula
C37H51N9O10S
Met-Glu-His-Phe-Pro-Gly-Pro: an ACTH fragment (4-7) joined to Pro-Gly-Pro. Sequence from Dolotov et al. 2006; mass checked against PubChem (CID listed as ACTH (4-7), Pro-Gly-Pro-).

BDNF in the hippocampus

A 2006 paper in Brain Research found that a single application of 50 micrograms per kg raised BDNF protein in the rat hippocampus by up to 1.4-fold, with 1.6-fold more trkB phosphorylation. At the mRNA level, exon III BDNF rose 3-fold and trkB 2-fold. Treated animals also showed more conditioned avoidance reactions. The authors suggested that Semax affects cognition by modulating the BDNF and trkB system.

Changes after a single dose of Semax in rat hippocampus

  • BDNF protein1.4 x
  • trkB phosphorylation1.6 x
  • trkB mRNA2 x
  • BDNF exon III mRNA3 x
Fold increase over control reported by Dolotov et al., Brain Research 2006, after a single application at 50 micrograms per kg. BDNF protein and trkB phosphorylation are the maximal increases reported.

After ischemic injury

A 2017 study ran a transcriptome analysis of the cerebral cortex in rats with focal cerebral ischemia given Semax or PGP alone. The immune response was the process most clearly affected. Semax enhanced the antigen presentation pathway and increased expression of the immunoglobulin heavy chain gene. PGP on its own attenuated immune activity and suppressed neurotransmission.

A transcriptome study in rats with focal ischemia

  1. 1

    Model

    Rats with focal cerebral ischemia were treated with Semax or the PGP tripeptide.

  2. 2

    Method

    Genome-wide analysis of the cerebral cortex found differentially expressed genes.

  3. 3

    Result

    The immune response was the process most affected, including antigen presentation and interferon signaling.

  4. 4

    Interpretation

    The authors propose the neuroprotection runs through neuroimmune crosstalk.

Summary of Medvedeva et al., Mol Genet Genomics 2017, which used rats with focal cerebral ischemia.

Limits

These are gene and protein expression results in rats. They suggest mechanisms, and they do not demonstrate cognitive benefit or neuroprotection in people. A 2016 chemistry paper on how acetylation of the N-terminus changes Semax's binding of copper and zinc is a reminder that small structural details alter the behavior of the molecule, which is one reason batch identity matters.

References

  1. Dolotov OV et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res 2006.
  2. Medvedeva EV et al. Semax, an analog of ACTH(4-7), regulates expression of immune response genes during ischemic brain injury in rats. Mol Genet Genomics 2017.
  3. Magri A et al. Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. J Inorg Biochem 2016.

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