Pinealon

What Is Pinealon?

Pinealon is a synthetic tripeptide with the sequence Glu-Asp-Arg (EDR), studied as a short peptide bioregulator with antioxidant and neuroprotective activity. It was characterized in laboratory work as able to limit the build-up of reactive oxygen species in several cell types.^[1]

Pinealon belongs to a family of very short peptides, mostly two to four amino acids long, studied largely by Vladimir Khavinson and colleagues. A 2020 review describes the EDR peptide as having established neuroprotective properties, activating the expression of genes and the synthesis of proteins involved in maintaining neuronal function, and reducing neuronal apoptosis in in-vitro and in-vivo studies.^[2]

In the Russian gerontology literature, pinealon is grouped with other short neuroprotective peptides such as semax and cortagen, and contrasted with polypeptide complexes extracted from animal brain tissue.^[3] Unlike those extracts, pinealon is a single, chemically defined molecule.

Pinealon is often studied alongside the tetrapeptides from the same research school. In the same set of HeLa cell experiments, fluorescence-labeled pinealon, epitalon (Ala-Glu-Asp-Gly) and testagen (Lys-Glu-Asp-Gly) all entered the cell nucleus, and each showed its own pattern of binding to short DNA sequences.^[4] This shared focus on gene regulation is the main reason these peptides are discussed together.

Chemical Structure and Molecular Identity

Pinealon is a linear tripeptide of L-glutamic acid, L-aspartic acid and L-arginine joined by two peptide bonds, with a free amine at the N-terminus and a free carboxylic acid at the C-terminus. PubChem (CID 10273502) lists the molecular formula C15H26N6O8 and a molecular weight of 418.40 g/mol.

The molecule is small and highly polar. Two of its three residues carry acidic side chains (glutamate and aspartate), while arginine contributes a strongly basic guanidino group. PubChem’s computed XLogP of -6.1 reflects very high water solubility and low lipophilicity.

Key identifiers

• CAS number: 175175-23-2
• InChIKey: QPRZKNOOOBWXSU-CIUDSAMLSA-N
• Synonyms: Glu-Asp-Arg, EDR peptide, L-glutamyl-L-aspartyl-L-arginine, H-Glu-Asp-Arg-OH

Pinealon should not be confused with longer peptides that happen to contain the Glu-Asp-Arg motif, or with synthetic arginine-aspartate peptides designed for other purposes. The name refers specifically to the free tripeptide EDR.

Research History and Development

Pinealon research comes almost entirely from Russian gerontology groups, beginning with studies of hypoxia and oxidative stress and later extending to gene regulation and neurodegeneration models. Much of the work appears in the journal Advances in Gerontology and in papers co-authored by Khavinson.

A 2008 study compared several short regulatory peptides, including vilon, epitalon, vesugen and pinealon, in an experimental model of hypobaric hypoxia and reported antihypoxic properties for all four, with pinealon showing the most pronounced effect.^[5] A 2011 paper then described its effects on reactive oxygen species, cell death and the cell cycle in cultured neurons and other cells.^[1]

Later reviews placed pinealon among short peptides proposed as multitarget agents for Alzheimer’s disease research, alongside Lys-Glu, Glu-Trp, Lys-Glu-Asp and others.^[6][2] A 2026 orthopaedics review published outside Russia mentioned pinealon with epithalon and delta sleep-inducing peptide as agents discussed for circadian and mitochondrial targets, while noting a general lack of clinical trials for these peptides.^[7]

Mechanisms Studied in Research

Two main mechanisms have been proposed for pinealon: reduction of oxidative stress and direct interaction with DNA and chromatin that may alter gene expression. Both rest largely on cell-culture and biophysical experiments.

Antioxidant and cell-survival effects

In cerebellar granule cells, neutrophils and PC12 pheochromocytoma cells exposed to oxidative stress, pinealon restricted reactive oxygen species accumulation in a concentration-dependent way and reduced necrotic cell death. The protective effect was accompanied by delayed ERK 1/2 activation and changes in the cell cycle. Because cell-cycle effects continued at concentrations above those that saturated the antioxidant effect, the authors proposed that pinealon also acts directly on the genome.^[1] In hypoxia experiments, its protective action was attributed less to blocking reactive oxygen species and more to stimulating internal antioxidant enzymes and possibly limiting NMDA-mediated excitotoxicity.^[5]

Nuclear entry and DNA binding

Fluorescence-labeled pinealon entered the cytoplasm, nucleus and nucleolus of HeLa cells. In vitro, it quenched the fluorescence of labeled deoxyribooligonucleotides in a sequence-dependent way, binding preferentially to sequences containing CNG and CAG sites, which are targets of cytosine methylation.^[4] Spectral, NMR, viscosity and molecular dynamics studies indicated that EDR can partly enter the major groove of DNA and interact with guanine N7 and O6 atoms, and that magnesium ions promote this interaction.^[8]

Proposed signaling targets

A 2020 review proposed that EDR binds histone proteins or nucleic acids and may change MAPK/ERK signaling and the synthesis of caspase-3, p53, the antioxidant enzymes SOD2 and GPX1, the transcription factors PPARA and PPARG, serotonin and calmodulin.^[2] These links are presented as hypotheses rather than established pathways.

Key Findings From Published Studies

Published findings on pinealon are mostly from cell and animal models, with a few small human studies; no large randomized controlled trials appear in the indexed literature. Results should be read with that limitation in mind.

In-vitro studies

• In cultured cerebellar granule cells, neutrophils and PC12 cells under oxidative stress, pinealon lowered reactive oxygen species levels and necrotic cell death.^[1]
• According to a 2020 review, EDR reduced the elimination of dendritic spines in neuronal cultures from mouse models of Alzheimer’s and Huntington’s disease, and promoted antioxidant enzyme synthesis in rat cerebellar neuron cultures.^[2]

Animal studies

• In a hypobaric hypoxia model, pinealon showed the strongest antihypoxic effect of four short peptides tested, and it increased neuronal resistance to hypoxic stress in experiments with prenatal hypoxia.^[5]
• The same 2020 review states that EDR normalized behavioral responses in animal studies.^[2]

Human studies

• The 2020 review reports that EDR improved memory problems in elderly patients, citing earlier clinical work by the same research group.^[2]
• In a comparative monitoring study of 110 people of different ages, oligopeptide preparations containing Lys-Glu-Asp and Glu-Asp-Arg showed the most pronounced effect on biological age indicators when the two were combined, and were rated among the safest of the techniques compared.^[9]

The human data come from small studies by a single research school, and the abstracts do not describe randomized, blinded designs. Independent replication outside this group is lacking.

Since studies concern the defined EDR tripeptide, researchers typically confirm identity and purity using HPLC and mass spectrometry certificates of analysis.

Regulatory and Research Status

Pinealon is not approved by the US Food and Drug Administration for any medical use and has no approved indication in the United States. It is available as a research chemical and appears in the scientific literature as an investigational short peptide.

Most published studies come from Russian research groups, especially work led by Khavinson, and many appear in Russian-language journals with English abstracts. Reviews from outside this school mention pinealon only briefly and note that clinical evidence is limited.^[7]

Open questions include its stability and fate in the body, whether the DNA-binding interactions seen in vitro occur in living tissue, and whether the cell and animal findings can be reproduced by independent laboratories using controlled study designs. In the 110-person geroprotection comparison, the strongest effect was reported when pinealon was combined with another peptide preparation, which makes its individual contribution hard to isolate.^[9]