Cortagen

A synthetic tetrapeptide (Ala-Glu-Asp-Pro) from the Khavinson bioregulator program, designed from amino-acid analysis of the Cortexin brain-cortex extract and studied in rodents and tissue culture for cortical explant growth, nerve regeneration, and antioxidant effects.

Also referenced as: Cortagene, Ala-Glu-Asp-Pro, AEDP tetrapeptide, L-alanyl-L-glutamyl-L-aspartyl-L-proline

Also appears in: Longevity

What is Cortagen?

Cortagen is a synthetic tetrapeptide with the sequence Ala-Glu-Asp-Pro (AEDP; C17H26N4O9, about 430 Da). It was produced by the Saint Petersburg Institute of Bioregulation and Gerontology through what its developers call directed synthesis: the amino-acid composition of Cortexin, a cattle-brain cortex extract registered as a drug in Russia, was used to design a short defined peptide meant to stand in for the extract (Anisimov et al., Neuro Endocrinology Letters, 2004;25(1–2):87–93). It is the cerebral-cortex member of the Khavinson “cytogen” series, alongside Epitalon (Ala-Glu-Asp-Gly, pineal), Livagen (Lys-Glu-Asp-Ala, liver), and Vilon (Lys-Glu, thymus), and differs from Epitalon only in its C-terminal residue, proline in place of glycine.

It reaches the research market on the strength of that lineage. Cortexin has more than two decades of Russian clinical use, Epitalon has a large longevity following, and Cortagen sits between them as a defined, synthesizable molecule with a cortical pedigree. Unlike Cortexin, no registration of it as a medicine anywhere appears on the public record, and the patent that once covered it in the United States has lapsed.

How it works

The developers’ framework holds that short peptides enter the nucleus and modulate gene transcription in the tissue whose extract they were designed from. The data specific to Cortagen come almost entirely from one institute and its collaborators:

• Tissue-specific stimulation of cortical explants. In organotypic culture, Cortagen stimulated the growth of explants from rat brain cortex, while Epithalon, Livagen, and Vilon stimulated explants from subcortical structures, liver, and thymus respectively; each synthetic peptide acted on the tissue whose natural peptide complex had supplied its amino-acid analysis (Khavinson, Bulletin of Experimental Biology and Medicine, 2001;132(2):807–808; Khavinson et al., Advances in Gerontology, 2002;9:95–100). The patent describes the same assay in chicken-embryo cortex explants, with a roughly 40% increase in explant area at 20 ng/mL.
• Broad transcriptional effects, measured in heart rather than brain. The one genome-scale experiment on the peptide profiled 15,247 transcripts in the hearts of 6-month-old female CBA mice after five consecutive daily injections. It found 234 clones (1.53%) with significantly altered expression, mapping to 110 known genes across functional categories, with maximum changes of +5.42-fold and −2.86-fold (Anisimov et al., Neuro Endocrinology Letters, 2004;25(1–2):87–93). The readout tissue was chosen because of cardiovascular observations the authors attribute to the peptide, so it says little about cortical neurons directly.
• Redox effects in rat brain. Injections of Cortagen or Epithalon reduced lipid-peroxidation products and oxidative protein modification in rat serum and cerebral cortex, although the same abstract reports that endogenous antioxidant activity fell in parallel, so “antioxidant” is a loose label for what was measured (Kozina, Bulletin of Experimental Biology and Medicine, 2007;143(6):744–746). In a chronic cerebral ischemia model both Cortexin and Cortagen prevented excess lipid-peroxidation activation and loss of antioxidant activity in brain tissue (Zarubina and Shabanov, Eksperimental’naia i Klinicheskaia Farmakologiia, 2011;74(2):8–15).
• Immune-cell assays, where Cortagen is the weak sibling. In the institute’s immunology series Cortagen was consistently the least active of the three cytogens: it activated interleukin-2 mRNA in mouse splenocytes less than Vilon or Epithalon (Kazakova et al., Bulletin of Experimental Biology and Medicine, 2002;133(6):614–616), produced no comitogenic effect on thymocyte proliferation where the other two did (Khavinson et al., Bulletin of Experimental Biology and Medicine, 2002;133(5):497–499), and modulated hypothalamic IL-2 expression in vivo depending on route and timing (Kazakova et al., Bulletin of Experimental Biology and Medicine, 2005;139(6):718–720).
• Chromatin decondensation in aged human lymphocytes, ex vivo. In cultured leukocytes from donors aged 75–88, Cortagen was one of several short peptides that activated ribosomal genes and decondensed densely packed heterochromatin, a finding its authors read as release of age-silenced genes (Khavinson, Lezhava and Malinin, Bulletin of Experimental Biology and Medicine, 2004;137(1):78–81; Lezhava et al., Georgian Medical News, 2023;(335):79–83). These are cell-culture experiments on human cells, not studies of treated people.

Whether the proposed peptide-DNA interaction is real for this sequence is not established. The docking and biophysical binding work from the same program concerns related peptides (AEDG, AEDL, KED); a PubMed search for Cortagen together with DNA or docking returns only the 2004 microarray paper, and no independent laboratory has reported a direct Cortagen-DNA interaction.

Research status

Cortagen is a small, old, single-network literature. A PubMed search returns 15 records in all fields (only four carry the name in the title), spanning 2000 to 2023. The most recent in-vivo experiment dates to 2016; the most recent experiment of any kind is the 2023 Tbilisi lymphocyte-culture paper, from a group that has collaborated with the Saint Petersburg institute since the early 2000s. Every record comes from the Saint Petersburg Institute of Bioregulation and Gerontology or from Russian and Georgian groups working with it or on its peptides (the Pavlov Institute of Physiology, the Institute of Experimental Medicine, the Kirov Military Medical Academy, the Chita medical academy, Tbilisi State University). None comes from an independent Western laboratory. There are no registered clinical trials: a ClinicalTrials.gov intervention search returns zero studies.

The strongest in-vivo result is peripheral, not cortical. After transection and suturing of the rat sciatic nerve, 10 µg/kg Cortagen intramuscularly for 10 days increased the growth rate of regenerating fibers by 27% and their conduction velocity by 40% (Turchaninova et al., Bulletin of Experimental Biology and Medicine, 2000;130(12):1172–1174). A follow-up reported a delayed effect on the restoration of injured nerve function (Kolosova et al., Doklady Biological Sciences, 2002;384:183–184). These are short reports from a single laboratory, without blinding details, and they have not been repeated elsewhere.

Cerebral ischemia models. In rats with chronic brain ischemia stratified by hypoxia tolerance, both Cortexin and Cortagen accelerated recovery of disturbed individual behavior and limited oxidative damage in brain tissue (Zarubina and Shabanov, 2011, above). The same authors later reported that “neurospecific peptide preparations” reduced neurological deficit and exerted antioxidant effects during the early and late phases of ischemic preconditioning in male Wistar rats; the abstract names no compound, but PubMed indexes the paper for Cortexin, Cortagen, and Noopept (Zarubina and Shabanov, Bulletin of Experimental Biology and Medicine, 2016;160(4):448–451). Both are rodent behavioral and biochemical studies; as far as their abstracts report, neither measured neuronal survival by histology in a way that would support the “neuronal survival” shorthand often attached to the compound.

A negative result worth knowing. In neonatally hypophysectomized chicks and in old birds, 40 days of Epithalon fully reversed the anemia, immune deficiency, hypercoagulation, and inhibited fibrinolysis that followed surgery, while Cortagen, which differs from Epithalon by a single terminal residue, had no effect on any of the parameters studied (Kuznik et al., Advances in Gerontology, 2008;21(3):372–381). The developers cite this as evidence of tissue specificity; it is equally a reminder that the two peptides should not be treated as interchangeable, and that Epitalon’s data do not transfer to Cortagen.

Human data exist only in a patent and an unreferenced sentence. The 2004 microarray paper asserts that in humans Cortagen showed a pronounced therapeutic effect on recovery of injured peripheral nerve tissue, but cites no study for the claim, and no peer-reviewed human trial of the peptide is indexed on PubMed. The only human results on record are in US Patent 7,189,701 (priority 1999, granted 2007, now expired): 35 patients with long-standing complications of head injury split into standard care (n=10), standard care plus 1 µg Cortagen intramuscularly daily for 10 days (n=15), and standard care plus Cerebrolysin (n=10), with better proof-reading test scores and EEG alpha-index in the peptide arm; and a 12-patient single-arm series in vascular dementia given 3 µg intramuscularly daily for 30 days, with pre-treatment values as the only control. The patent describes no randomization, no blinding, and no statistical methods beyond isolated p-values. Applicant-reported patent data are not peer-reviewed evidence and should not be described as a clinical trial.

Safety data are preclinical and developer-reported. The patent reports no deaths or changes in mice after single intramuscular doses of 1–5 mg/kg, and no pathological findings in rats dosed daily for 90 days at up to 3 mg/kg or for 6 months at up to 1 mg/kg. No published human pharmacokinetic, tolerability, or adverse-event data exist.

Common dosage forms

• Lyophilized powder in vials, most often 20 mg and sometimes 10 mg, intended for reconstitution. This is the format in which research vendors list the compound.
• Oral or intranasal formats were contemplated in the patent, which lists parenteral, intranasal, and oral formulations, but no published study used them and they are not a standard market presentation for this peptide. Capsule products in the Khavinson bioregulator line labeled for the brain (such as Cerluten) contain a cortex extract, not synthetic Cortagen.

No pharmaceutical presentation of Cortagen appears on the public record in any jurisdiction, so there is no reference product against which a research vial could be compared.

Key considerations

• Regulatory status: none. Cortagen is not FDA-approved, is not in clinical development, and has no registered trials. Its US composition-of-matter patent has expired. Unlike Cortexin, which is a registered prescription drug in Russia, no drug registration for Cortagen itself appears on the public record in Russia or elsewhere; it is sold purely as a research chemical. The Research Market status reflects the absence of US approval or any development program aimed at approval.
• The evidence is thin, old, and single-network. Fifteen indexed papers, most under four pages, all from one institute’s collaborator network, with the last in-vivo experiment in 2016 and no independent replication. The organotypic-culture, microarray, and redox findings are developer-generated, and the one in-vivo head-to-head on systemic endpoints showed Cortagen inactive where Epitalon was active.
• Mechanism is a hypothesis, not a finding. The nuclear-penetration and peptide-DNA binding model that underpins the whole bioregulator family has not been demonstrated for this sequence by biophysical methods, and the gene-expression data that exist were collected in mouse heart. Claims about neuronal survival, cognition, or longevity in humans have no peer-reviewed support.
• Human “data” is patent prose. The 35-patient head-injury series and the 12-patient dementia series live only in a patent filing, without randomization, blinding, or described statistics. The 2004 paper’s statement about human nerve recovery is unreferenced. Anyone presenting Cortagen as clinically tested is relying on these.
• Naming and abbreviation collisions. Cortagen (defined synthetic tetrapeptide), Cortexin (cattle-cortex extract, Russian injectable drug), Cerluten (calf-cortex extract, oral capsules), and Cerebrolysin (porcine-brain peptide mixture) are routinely conflated; Cortexin’s clinical record does not belong to Cortagen. The abbreviation “AEDP” is also the name of an unrelated chemistry reagent, 3-[(2-aminoethyl)dithio]propionic acid, so literature searches on the four-letter code return papers that have nothing to do with the peptide. PubMed files the compound under the supplementary concept “alanyl-glutamyl-aspartylprolyine” (NLM’s spelling), and the spellings “cortagene” and “Kortagen” appear in Russian-language sources.