# Cortagen

> Cortagen is a synthetic tetrapeptide, Ala-Glu-Asp-Pro, with the formula C17H26N4O9 and a molecular weight of 430.4 g/mol. It was designed from peptide complexes of the cerebral cortex and belongs to the short peptide bioregulators. Published research consists of rat and mouse studies and cell experiments on tissue growth, immune signaling and oxidative stress. It is not an FDA-approved drug.

Canonical: https://peptideproperties.com/compounds/cortagen/

## Identity

- **Class:** Short Peptide Bioregulators
- **Also known as:** Ala-Glu-Asp-Pro
- **Molecular formula:** C17H26N4O9
- **Molecular weight:** 430.4 g/mol
- **Monoisotopic mass:** 430.1700 Da
- **CAS number:** 335591-03-2
- **PubChem CID:** 18439621
- **InChIKey:** PLTRIMAUDDQYRV-NAKRPEOUSA-N
- **Sequence:** AEDP
- **Sequence notes:** No modifications; free N-terminal amine and free C-terminal carboxylic acid.

## Key facts

- Class: short peptide bioregulator; synthetic tetrapeptide (cytogen)
- Sequence: H-Ala-Glu-Asp-Pro-OH (AEDP), four residues
- Formula C17H26N4O9; molecular weight 430.4 g/mol (PubChem CID 18439621)
- CAS 335591-03-2
- Origin: synthesized based on peptide complexes from the cerebral cortex
- Evidence base: rat and mouse studies, explant cultures and cell experiments
- Regulatory status: not approved by the FDA

## What Is Cortagen?

Cortagen is the tetrapeptide Ala-Glu-Asp-Pro, a synthetic short peptide studied for tissue-specific effects on the cerebral cortex. A 2001 paper grouped it with epitalon, livagen and vilon as synthetic peptides, or cytogens, each modeled on a natural peptide complex from a particular tissue.[1]Cortagen's sequence was reported in mouse immunology studies that compared it directly with vilon (Lys-Glu) and epitalon (Ala-Glu-Asp-Gly).[2] Much of its literature uses this same three-peptide comparison, which makes it possible to see where Cortagen behaved differently from its better-known relatives.Most published work on Cortagen covers four areas: tissue-specific growth of explants in culture, immune signaling in thymocytes, splenocytes and macrophages, chromatin changes in white blood cells from older people, and oxidative stress in the rat brain. All of it is preclinical or laboratory work.

## Chemical Structure and Molecular Identity

Cortagen is a linear tetrapeptide of L-alanine, L-glutamic acid, L-aspartic acid and L-proline with free amino and carboxyl termini. PubChem (CID 18439621) lists the molecular formula C17H26N4O9, a molecular weight of 430.4 g/mol, the InChIKey PLTRIMAUDDQYRV-NAKRPEOUSA-N and CAS number 335591-03-2. This formula matches the unmodified sequence Ala-Glu-Asp-Pro.The molecule is strongly hydrophilic, with a computed XLogP of -6.5, reflecting the acidic side chains of glutamic acid and aspartic acid plus the free C-terminal carboxyl group on proline. Its C-terminal proline is the only structural difference from epitalon, which ends in glycine.
### Related sequences
Cortagen shares its first three residues, Ala-Glu-Asp, with epitalon. Other bioregulator peptides carry a Glu-Asp core with different flanking residues, for example prostamax (Lys-Glu-Asp-Pro), which shares Cortagen's C-terminal Asp-Pro. These are distinct compounds with different formulas and molecular weights, and results for one should not be assigned to another.

## Research History and Development

Cortagen was developed as part of a program that designed short synthetic peptides from the amino acid makeup of tissue-derived peptide complexes. In organotypic culture, Cortagen stimulated the growth of explants from the rat brain cortex, while epitalon, livagen and vilon stimulated explants from subcortical structures, liver and thymus, respectively. The authors described this as a tissue-specific effect, with each peptide acting on the tissue whose peptide complex was used for its synthesis.[1]A related study compared these synthetic peptides with polypeptide preparations isolated from the cerebral cortex, pineal gland, liver and thymus in explant cultures from rats of different ages, and again reported tissue-specific effects.[3]From the early 2000s, research on Cortagen expanded into immunology, using thymocytes, splenocytes and macrophages from mice, and later into brain oxidative stress and ischemia models in rats. The later brain studies returned to the compound's cortical origin: a 2007 study grouped Cortagen with epitalon as bioactive tetrapeptides acting on free-radical processes,[4] and a 2011 study tested it against a cortex-derived polypeptide preparation in chronic ischemia.[5] Most of these studies were published in Russian experimental biology and gerontology journals.

## Mechanisms Studied in Research

Studies have examined Cortagen's effects on interleukin-2 gene expression, immune-cell signaling, chromatin structure and lipid peroxidation, without identifying a specific receptor. In several head-to-head comparisons it was less active than vilon or epitalon.
- Thymocyte signaling: in mouse thymocytes, vilon had the strongest comitogenic effect and epitalon a weaker one, while Cortagen produced no such effect. Vilon also stimulated sphingomyelinase activity in thymocyte membranes more than epitalon or Cortagen.[2]
- Interleukin-2 gene expression: in splenocytes from CBA mice, all three peptides activated interleukin-2 mRNA synthesis without other stimuli, with Cortagen producing a less pronounced effect than vilon and epitalon.[6] In rats, in situ hybridization showed that the peptides modulated interleukin-2 gene expression in some hypothalamic structures, depending on timing and route.[7]
- Macrophage factors: Cortagen, vilon and epitalon had opposite modulating effects on lymphocyte-activating factor production by resident versus lipopolysaccharide-stimulated macrophages from young and old mice.[8]
- Chromatin: in white blood cells from people aged 75 to 88, Cortagen and four other short peptides activated ribosomal genes and decondensed tightly packed heterochromatin.[9]Taken together, these studies suggest Cortagen can influence cytokine gene expression but is not uniformly immunostimulatory. Its reported effects varied with cell type, the activation state of the cells and the age of the animals they came from.[2][6][8] The oxidative stress studies point to a second line of activity, involving lipid peroxidation in the brain, described in the next section.

## Key Findings From Published Studies

Published findings on Cortagen come from rodent experiments and cell studies; no controlled human trials were found. The main results are grouped below by model.
### Explant culture
In organotypic cultures, Cortagen stimulated growth of explants from the rat brain cortex, consistent with the tissue-specific design of the cytogen peptides.[1] Comparable tissue-specific effects were reported in explants from rats of different ages.[3]
### Immune cells in mice
In mouse thymocytes, Cortagen did not enhance proliferation in response to a mitogen, unlike vilon and, to a lesser degree, epitalon.[2] In splenocytes from CBA mice, it activated interleukin-2 mRNA synthesis, but less strongly than the other two peptides, with the response depending on concentration and treatment duration.[6] In peritoneal macrophages, lipopolysaccharide-stimulated production of lymphocyte-activating factors was lower in old mice, and the short peptides modulated this production in opposite directions in resting and stimulated cells.[8]
### Oxidative stress in rats
A 2007 study reported that treating rats with Cortagen or epitalon decreased lipid peroxidation products and reduced oxidative modification of proteins. The abstract notes this was paralleled by suppression of antioxidant activity in rat serum and cerebral cortex.[4]
### Chronic brain ischemia in rats
In rats with chronic brain ischemia, divided into high and low hypoxia-resistance groups, Cortagen and a cortex-derived polypeptide preparation both accelerated recovery of disturbed individual behavior. Both also prevented excessive activation of lipid peroxidation and a drop in antioxidant activity in brain tissue.[5]
### Chromatin in cells from older people
In leukocytes from people aged 75 to 88, all five peptides tested released genes repressed by age-related condensation. Changes in chromosome 1 pericentromeric chromatin were reported for epitalon, livagen and prostamax, but not for Cortagen.[9]Because Cortagen differs from epitalon only at its final residue, researchers typically confirm identity with mass spectrometry and HPLC data on a certificate of analysis.

## Regulatory and Research Status

Cortagen is not approved by the US Food and Drug Administration and is handled as a research compound in the United States. Its literature is modest in size, spans roughly 2001 to 2011 in the sources reviewed here, and comes largely from one network of collaborating research groups.Important gaps remain. The abstracts reviewed here contain no human clinical trials, no pharmacokinetic or toxicology data, and no defined molecular target. Several studies report Cortagen as weaker than vilon or epitalon on immune measures, so findings for those peptides should not be extended to it.[2][6]The chromatin work used cells from older people rather than treating human participants, and the oxidative stress and ischemia findings come from rat models.[9][5]

## FAQ

**What is the sequence of Cortagen?**
Cortagen is the tetrapeptide Ala-Glu-Asp-Pro (one-letter code AEDP), with a free N-terminal amine and a free C-terminal carboxylic acid. PubChem (CID 18439621) lists its formula as C17H26N4O9 and its molecular weight as 430.4 g/mol, which matches that unmodified sequence. Its CAS number is 335591-03-2.

**How is Cortagen different from epitalon?**
Cortagen (Ala-Glu-Asp-Pro) and epitalon (Ala-Glu-Asp-Gly) share their first three residues but end in proline and glycine, respectively. They were designed for different tissues: Cortagen stimulated rat brain cortex explants, while epitalon acted on subcortical explants. In mouse immune studies, Cortagen was generally less active than epitalon.

**Is Cortagen FDA approved?**
No. Cortagen is not approved by the US Food and Drug Administration for any use and is handled as a research compound in the United States. Its published literature consists of rat and mouse experiments, explant cultures and cell studies, with no controlled human clinical trials identified in PubMed.

**What does the research on Cortagen show?**
Research on Cortagen is preclinical. It stimulated growth of rat brain cortex explants, modulated interleukin-2 gene expression in mouse and rat cells, and reduced lipid peroxidation markers in rats, including in a chronic brain ischemia model. In mouse thymocytes it showed no comitogenic effect, unlike vilon and epitalon.

**What is the molecular weight of Cortagen?**
The molecular weight of Cortagen is 430.4 g/mol, according to PubChem (CID 18439621). Its molecular formula is C17H26N4O9 and its InChIKey is PLTRIMAUDDQYRV-NAKRPEOUSA-N. The tetrapeptide is highly polar, with a computed XLogP of -6.5, because of its acidic glutamic and aspartic acid residues.

## References

1. Khavinson VK. Tissue-specific effects of peptides. Bulletin of experimental biology and medicine 2001. PMID: 11713572
2. 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
3. Khavinson VKh, Malinin VV, Chalisova NI, et al. [Tissue-specific action of peptides in tissue culture of rats of various ages]. Advances in gerontology = Uspekhi gerontologii 2002. PMID: 12096446
4. Kozina LS. Effects of bioactive tetrapeptides on free-radical processes. Bulletin of experimental biology and medicine 2007. PMID: 18239817
5. Zarubina IV, Shabanov PD. [[cortex polypeptide preparation] 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
7. Kazakova TB, Barabanova SV, Novikova NS, et al. Synthesis of IL-2 mRNA in cells of rat hypothalamic structures after injection of short peptides. Bulletin of experimental biology and medicine 2005. PMID: 16224591
8. Gumen AV, Kozinets IA, Shanin SN, et al. Production of lymphocyte-activating factors by mouse macrophages during aging and under the effect of short peptides. Bulletin of experimental biology and medicine 2006. PMID: 17426849
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