Pinealon

Pinealon is the synthetic tripeptide Glu-Asp-Arg. Primary papers usually call it EDR. It is one of a series of short peptides created at the St Petersburg Institute of Bioregulation and Gerontology. These are studied as so-called peptide bioregulators. The group also includes epitalon (Ala-Glu-Asp-Gly), vesugen and testagen. This research program proposes that the peptide binds DNA and histone proteins directly, in a sequence-selective way.

In that view, it does not act at a cell-surface receptor. No receptor for it has been reported. By the standards of better-studied peptides, published work is thin. Most of it comes from one group and those who work with it.

Sequence, aliases and the salt-form note come from PubChem.

Published work on pinealon falls into five areas. Each summary below states the model used. The body of work is small. A PubMed search for the peptide and its EDR name returns fewer than 50 records. Several are false hits on the same three-letter string. A large share of the rest come from V. Kh.

Khavinson's group or labs working with the same institute. Several animal studies appear only in Russian-language journals with brief English abstracts. Several papers also test pinealon alongside other short peptides, not on its own. So it is not always clear which effects come from this sequence.

Oxidative stress in cell culture

The most direct cell work used rat cerebellar granule cells, neutrophils and PC12 pheochromocytoma cells. The cells were put under oxidative stress. The team then measured reactive oxygen species and necrotic cell death. The peptide limited the build-up of reactive oxygen species. The effect depended on concentration.

It also cut cell death, measured with propidium iodide. ERK 1/2 activation was delayed, and the cell cycle changed. The cell-cycle change went on at concentrations above those that saturated the effect on reactive oxygen species. So the authors proposed a second action at the level of the genome (Khavinson et al., 2011).

Interaction with DNA and chromatin

Fluorescein-labeled pinealon, epitalon and testagen all entered the cytoplasm, nucleus and nucleolus of HeLa cells. In parallel binding tests, each peptide quenched the fluorescence of labeled deoxyribooligonucleotides. The degree of quenching differed by sequence. Binding favored CNG-containing sequences and was sensitive to cytosine methylation status (Fedoreyeva et al., 2011).

An independent physical-chemistry group studied the same binding. It used spectroscopy and nuclear magnetic resonance. It also used viscosimetry and molecular dynamics. It reported that the peptide partly enters the major groove, with contacts at guanine N7 and O6. Magnesium ions promoted this binding (Silanteva et al., 2019).

Neuronal culture models

One study used primary mouse hippocampal neurons exposed to amyloid beta. There, 200 ng/mL of the tripeptide raised the number of mushroom spines by 71 percent. That brought the count back to the untreated level. A related tripeptide gave a 20 percent rise (Kraskovskaya et al., 2017). A 2024 study used a different model.

It made cortical neurons from the skin fibroblasts of elderly donors by transdifferentiation. The authors reported more primary dendrites and greater total dendrite length with three short peptides. The largest drop in a marker of oxidative DNA damage, 23 percent, came with this sequence, at p = 0.057 by the authors' own analysis; the other two peptides lowered it by 10 and 15 percent.

There was no change in mitochondrial or lysosomal activity, or in p16 levels (Kraskovskaya et al., 2024). In aging cultures of brain cortex cells, the peptide was reported to raise serotonin expression. Molecular docking was used to propose a binding site in the tryptophan hydroxylase gene (Khavinson et al., 2014). Organotypic pineal culture gave a contrasting finding. There, the tripeptide did not change expression of the proliferation marker Ki-67 or the apoptosis marker AIF. A related tetrapeptide raised Ki-67 and CGRP expression, and none of the peptides changed AIF (Khavinson et al., 2011).

Rodent models

One rat model loaded pregnant mothers with dietary methionine. This produced experimental hyperhomocysteinemia during pregnancy. Offspring of dams given the peptide were reported to do better in spatial orientation and learning tasks. Cerebellar neurons isolated from those offspring showed less build-up of reactive oxygen species. They also had fewer necrotic cells (Arutjunyan et al., 2012).

Russian-language reports describe antihypoxic activity in a hypobaric hypoxia model. Of four short peptides compared, the tripeptide was described as the most pronounced (Kozina, 2008). Other Russian-language reports cover behavioral and caspase-3 measurements in old rats under hypoxia or hypothermia. There, a polypeptide preparation had the larger effect on free-radical measures (Mendzheritsky et al., 2014; Mendzheritsky et al., 2015).

Mouse model of amyloid pathology and proposed epigenetics

In 5xFAD mice, this tripeptide and a related one were each given systemically every day for two months. Both tended to raise neuroplasticity measures, and both were reported to prevent loss of dendritic spines. The team also used molecular modeling and docking of the peptides into double-stranded DNA. This found candidate binding sites in the promoter regions of several genes.

The authors link these genes to the pathology (Khavinson et al., 2021). A review from the same group collects the proposed targets. They include caspase-3, p53 and superoxide dismutase 2. They also include glutathione peroxidase 1 and the PPAR transcription factors. The review openly says that the cell-entry and binding model is still an assumption (Khavinson et al., 2020).