Cortagen Research, Specifications & Scientific Information

Introduction

Cortagen is the cortical member of the Khavinson bioregulator series — Ala-Glu-Asp-Pro, four residues, 430 daltons — designed by directed synthesis from the amino acid composition of Cortexin, a natural brain cortex peptide preparation ^[3].

It is also the member of the series most often reported as the least active compound in an experiment, and that is the most useful thing about it. In splenocytes it produced the smallest effect on interleukin-2 transcription of the three peptides tested ^[6]. In thymocytes it produced no comitogenic effect at all, where Vilon was potent ^[7]. A series whose members always behave the same way tells a reader nothing about sequence; a series whose members separate — including by one of them doing nothing — is at least making claims that could be wrong.

The shared limitations of this literature apply and are stated once here. The primary work comes from the St Petersburg Institute of Bioregulation and Gerontology and collaborating Russian institutions; several papers are Russian-language; group sizes are small or unstated in the indexed abstracts; and none of the central findings has been independently replicated. No primary clinical report of this tetrapeptide has been identified, although one rodent paper asserts a human effect in passing without citing a source.

What Is Cortagen?

A synthetic tetrapeptide with free termini, AEDP in single-letter code: L-alanyl-L-alpha-glutamyl-L-alpha-aspartyl-L-proline. The originating group's own English-language work transliterates the name Korthagen as well as Cortagen, and at least one Russian-language paper uses Cortagene.

Its design parent is named explicitly in the microarray paper: the tetrapeptide was obtained by directed synthesis based on amino acid analysis of the natural brain cortex peptide preparation Cortexin ^[3]. That relationship — mixture first, single sequence second — is the same one that connects Thymalin to Thymogen and a pineal extract to Epitalon, and it carries the same caution: results obtained with the extract are not results about the tetrapeptide.

In the series' own tissue-matching experiment, explants from rat brain cortex, subcortical structures, liver and thymus were exposed to four peptides, and this one was reported to stimulate growth of the brain cortex explants while the others stimulated their own matched tissues ^[8].

Cortagen has not been approved by the U.S. Food and Drug Administration for any indication. No marketing application is on record in the United States, and no study of it appears on ClinicalTrials.gov.

Cortagen Specifications

PubChem carries the free tetrapeptide as compound identifier 18439621 with CAS registry number 335591-03-2, formula C17H26N4O9 and an average mass of 430.41 g/mol. No unique ingredient identifier resolves in the FDA/NCATS Global Substance Registration System. The sequence is given as Ala-Glu-Asp-Pro in the primary literature, and the name is transliterated Korthagen in the originating group's 2022 transporter review and Cortagene in at least one Russian-language paper. The C-terminal proline restricts backbone rotation, removes one backbone amide hydrogen, and permits cis as well as trans configuration of the preceding peptide bond, so material of a single sequence can exist as two slowly interconverting conformers. Reagent material supplied as a salt will not match the free-peptide mass above.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does Cortagen Work?

Not established, and for this compound the gap between the data and an account of mechanism is unusually visible, because the largest dataset points at an organ nobody predicted.

The microarray, and why it is odd. The compound was designed from a brain cortex preparation and its signature result is a peripheral nerve one. The transcriptional profiling was nonetheless carried out in heart. The stated reasoning is that effects on cardiovascular and cerebrovascular parameters had been observed, so the heart transcriptome was examined to look for a mechanism ^[3]. Expression of 15,247 transcripts was measured in female CBA mice after five consecutive daily injections; 234 clones — 1.53% of the total — changed significantly, corresponding to 110 known genes across several functional categories, with maximum up-regulation of 5.42-fold and maximum down-regulation of 2.86-fold.

A list of 110 differentially expressed genes is a description of the downstream state of a tissue. It is compatible with almost any upstream mechanism, including an indirect or non-specific one, and the paper does not narrow it.

The comparison inside that paper is the more informative part. Cardiac expression profiles induced by three peptides of the series and by melatonin were compared, and the authors report both common and specific effects ^[3]. Shared signatures across structurally different peptides argue for a shared, probably non-specific route; the specific components argue that sequence contributes something. The paper does not resolve the proportions.

A free-radical result that does not resolve. In rats, injections of this tetrapeptide and Epitalon reduced lipid peroxidation products and reduced oxidative modification of proteins in serum and cerebral cortex — while antioxidant activity in the same samples was suppressed ^[4]. Less oxidative damage alongside less antioxidant capacity is not an impossible combination, but it is not what a simple antioxidant mechanism predicts, and the paper reports it without reconciling the two.

No receptor is proposed, and no pharmacokinetic dataset exists. The rodent work used intramuscular administration at 10 micrograms per kilogram.

Preclinical Research on Cortagen

Animal research

Sciatic nerve regeneration in rats

The compound's signature result. Rats had the sciatic nerve transected and sutured, then received 10 µg/kg intramuscularly for ten days. Growth rate in the regenerating nerve fibres increased by 27% and conduction velocity by 40% relative to control ^[1].

Both endpoints are objective and quantitative, which is worth something. The report itself is very short, and the indexed abstract states neither group sizes nor statistical tests — so the two percentages stand without a measure of their precision. A follow-up in Doklady Biological Sciences is titled as describing a delayed effect on restoration of function in the same model; its indexed record carries no abstract at all, so no quantitative statement is made from it here ^[2].

Cardiac gene expression in mice

Described above: 15,247 transcripts, five daily injections, 234 significantly changed clones matching 110 known genes, compared against two sibling peptides and melatonin ^[3].

Free-radical endpoints in rats

Injections reduced lipid peroxidation products and oxidative modification of proteins in serum and cerebral cortex, with antioxidant activity suppressed in parallel ^[4].

Chronic cerebral ischaemia in rats

Rats with chronic cerebral ischaemia, stratified by high and low resistance to hypoxia, received either the natural preparation Cortexin or this synthetic tetrapeptide. Both were reported to accelerate the return of disturbed individual behaviour and to prevent excessive activation of lipid peroxidation and loss of antioxidant activity in brain tissue ^[5].

The stratification by hypoxia resistance is a genuine design feature — it tests whether an effect depends on baseline tolerance — and the extract-versus-peptide comparison is the kind that this literature needs more of. The indexed abstract gives no group sizes, no effect estimates and no statistical detail.

Findings in this section were obtained in rats and mice. Nothing in them establishes anything about humans.

Cortagen Mechanism of Action

In vitro research

The cell-culture record for this compound is mostly a record of it doing less than its siblings, and that is reported here as found.

Interleukin-2 transcription. In splenocytes from CBA mice, three peptides of the series activated interleukin-2 messenger RNA synthesis without any specific inducer. Vilon and Epitalon were the most potent; this tetrapeptide produced a less pronounced effect ^[6].

Thymocyte proliferation. In mouse thymocytes, Vilon had the strongest comitogenic effect and modulated the comitogenic activity of interleukin-1b; Epitalon was less potent; this tetrapeptide produced no such effects at all. It also stimulated membrane sphingomyelinase activity less than either ^[7].

Chromatin in lymphocytes from elderly donors. In leukocytes from subjects aged 75 to 88, this tetrapeptide was one of five tested. All five activated ribosomal genes and decondensed facultative chromatin; this one was not among those reported to decondense pericentromeric structural heterochromatin of chromosome 1 or chromosome 9 ^[9].

Organotypic brain cortex explants. Growth was stimulated, matched to the tissue the compound was designed from ^[8].

Everything in this section was observed in cultured cells or excised tissue. None of it establishes anything about an intact animal, and none of it about a person.

What Is Cortagen Being Researched For?

• Peripheral nerve regeneration — growth rate and conduction velocity after transection and suture in rats ^{[1, 2]}.
• Cerebral ischaemia models — behaviour and brain lipid peroxidation, against the parent extract ^[5].
• Gene expression profiling — the mouse heart microarray, including the cross-peptide comparison ^[3].
• Free-radical chemistry in rodents — peroxidation products, protein oxidation and antioxidant activity ^[4].
• Immune cell signalling in culture — interleukin-2 transcription, thymocyte proliferation, macrophage output ^{[6, 7]}.

None of that is research into, or evidence about, research-grade material supplied for laboratory use.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

Cortagen vs Related Compounds

Cortexin

The natural brain cortex polypeptide preparation this tetrapeptide was designed from — a mixture, not a molecule. The two were compared directly in a rat ischaemia study and reported as behaving similarly ^[5], which is a real comparison and still not a reason to transfer findings from the extract to the peptide.

Prostamax :: Lys-Glu-Asp-Pro — the same C-terminal proline with lysine in place of alanine at the N-terminus, and a prostatic rather than cortical assignment. The nearest available single-substitution pair in this batch, and no experiment testing the two against each other has been located. Cartalax :: Ala-Glu-Asp — this sequence with the proline removed. Another structural neighbour with a different tissue assignment and, again, no head-to-head experiment. Vilon and Epitalon :: The two peptides this one is most often tested beside, and the two it is most often reported as weaker than ^{[6, 7, 9]}.

Evidentiary position

Not approved by the U.S. Food and Drug Administration, no registered trial, no identified primary clinical report, and a signature rodent result published without group sizes or statistics.

No comparison of effect between these compounds is made on this page.

Chemical & Molecular Characteristics

Proline at the C-terminus governs the shape of this molecule. Its side chain closes onto its own backbone nitrogen, which removes an amide hydrogen the peptide would otherwise use to donate a hydrogen bond, and restricts rotation about the preceding bond. A four-residue peptide is normally conformationally shapeless in solution; this one is less so. The same residue permits the bond before it to adopt a cis as well as the usual trans configuration, so a single pure sequence can exist as two slowly interconverting species — which can appear in a chromatogram as a broadened or split peak for material that is genuinely one compound.

Alanine at the N-terminus contributes only a methyl group. It is the smallest chiral side chain in the standard set, and it is the entire structural difference between this tetrapeptide and Prostamax, which carries lysine there and is assigned to a different organ. The series' premise requires that difference to matter; nothing published tests it.

Net charge is acidic. With no basic side chain at all — alanine and proline contribute none — the glutamate side chain, the aspartate side chain and the C-terminal carboxyl leave the molecule with only its N-terminal amine to balance three acidic groups. It is therefore more strongly anionic at physiological pH than its lysine-containing siblings, which argues further against passive membrane crossing.

No aromatic residue, so no absorbance at 280 nm. Quantification relies on peptide-bond absorbance near 214 nm, where solvents and buffers also absorb.

Aspartate and glutamate bring isomers of identical mass. Both undergo alpha/beta and alpha/gamma rearrangement under thermal and acidic stress, producing species with the same formula and the same mass as the intended compound. Mass spectrometry confirms composition; it does not confirm connectivity, and for this molecule it does not report the cis/trans proline state either.

One register field is empty. CAS registry number 335591-03-2 and PubChem compound identifier 18439621 both resolve; no FDA/NCATS unique ingredient identifier does. That field is shown as unknown above rather than filled from a neighbouring substance.

Frequently Asked Questions

Scientific References

1. Turchaninova LN, Kolosova LI, Malinin VV, et al.. Effect of tetrapeptide cortagen on regeneration of sciatic nerve Bulletin of experimental biology and medicine; 2000. PMID 11276314
2. Kolosova LI, Moiseeva AB, Turchaninova LN, et al.. The delayed effect of cortagen on the restoration of injured nerve function Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections; 2002. PMID 12134478 doi:10.1023/a:1016098302564
3. Anisimov SV, Khavinson VKh, Anisimov VN. Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray Neuro endocrinology letters; 2004. PMID 15159690
4. Kozina LS. Effects of bioactive tetrapeptides on free-radical processes Bulletin of experimental biology and medicine; 2007. PMID 18239817 doi:10.1007/s10517-007-0230-8
5. Zarubina IV, Shabanov PD. [Cortexin and cortagen as correcting agents in functional and metabolic disorders in the brain in chronic ischemia] Eksperimental'naia i klinicheskaia farmakologiia; 2011. PMID 21476278
6. Kazakova TB, Barabanova SV, Khavinson VKh, et al.. In vitro effect of short peptides on expression of interleukin-2 gene in splenocytes Bulletin of experimental biology and medicine; 2002. PMID 12447482 doi:10.1023/a:1020210615148
7. Khavinson VKh, Rybakina EG, Malinin VV, et al.. Effects of short peptides on thymocyte blast transformation and signal transduction along the sphingomyelin pathway Bulletin of experimental biology and medicine; 2002. PMID 12420072 doi:10.1023/a:1019830308824
8. Khavinson VK. Tissue-specific effects of peptides Bulletin of experimental biology and medicine; 2001. PMID 11713572 doi:10.1023/a:1013058701974
9. Khavinson VKh, Lezhava TA, Malinin VV. Effects of short peptides on lymphocyte chromatin in senile subjects Bulletin of experimental biology and medicine; 2004. PMID 15085253 doi:10.1023/b:bebm.0000024393.40560.05

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.