PE-22-28 Peptide – A Novel Antidepressant Peptide
Depression is a major psychiatric disorder that adversely affects a person’s mood, behavior and mental health, mainly causing severe feelings of sadness, loneliness, and lack of interest in otherwise popular activities (1). As per recent statistics per World Health Organization (WHO), depression is highly common, affecting at least 5% of young adults and 5.7% of adults over 60 years of age, worldwide (2).
There are several antidepressants currently available in the market, however, these are either not always effective or may take several weeks of treatment before any therapeutic effects are observed. Tremendous research has been conducted over time to find a better cure, and as with most other cases, peptides seem to prove a better alternative.
One such peptide effective against depression and mental health disorder is called PE-22-28, a sortilin derived peptide.
PE-22-28 is a synthetic derivative of the naturally occurring protein called spadin (3).
Spadin is a natural peptide derived from sortilin, a protein found in abundance in the central nervous system of the body. Shorter analogous versions of spadin are more effective against combating depression than spadin itself. PE-22-28 peptide is one such shortened peptide derivative of this protein; similarlike spadin, PE-22-28 is known to exert its effect by acting on the TREK-1 receptor.
PE-22-28 Working Mechanism
What is the TREK-1 receptor?
TREK-1 (TWIK related potassium channel) receptor is a two pore potassium channel that was recently identified as a potential target to treat depression. In 2010, research(4) showed that when TREK-1 receptors were removed from mice, they became more resistant to depression.
TREK-1 receptor is primarily found in the brain region including prefrontal cortex and hippocampus, i.e., areas governing mood, memory and learning in humans. As seen in the image above, stimulating the TREK-1 receptor leads to reducing neuron excitability; whereas, reducing the receptor activity leads to increasing neuron excitability (5).
While mainly used in the study of antidepressant development, this receptor also plays a vital role in anesthesia, pain perception and protection of neurons.
PE-22-28 Peptide Role
Studies (3) in the past have demonstrated that spadin blocks the TREK-1 channel and exerts antidepressant activity, however, this effect stops within 7 hours of administration.
In order to improve the bioavailability and stability, scientists conducted several studies on spadin derivatives and analogs. One such study (3) was conducted on the seven amino acid spadin derivatives called PE-22-28.
PE-22-28, similar to spadin, binds to TREK-1 channel and blocks its activity, thereby producing mind stability and mood enhancing effects, with much more promising results than spadin alone. Duration of PE-22-28 effects remains up to 23 hours as opposed to 7 hours of spadin.
It was not until 2006 that compounds inducing antagonistic effects against TREK-1 receptors were known. This agent, which was of great interest in treating post stroke depression (PSD), was later discovered as Sortilin.
Research showed this compound released a 44 amino acid peptide in the bloodstream, called spadin i.e., PE-12-28, which was a natural blocking agent of TREK-1 receptor. Continued research then led to the discovery of the shorter, 7 amino acid peptide named PE-22-28, also known as ‘mini spadin’.
Biological Uses of PE-22-28
This compound has demonstrated various biological effects in humans, including:
- Possesses antidepressant properties
- May also assist in treating post stroke depression
- Increases regulation of neurogenesis
- Improves muscle function
- Possesses nootropic effects
The peptide has other added benefits including:
- Improved stability than spadin
- Faster acting than other similar TREK-1 blocking antidepressants
- Longer half life than spadin
Research and Clinical Studies
Studies Demonstrating Antidepressant Properties
As stated earlier, most of the antidepressants produce their effects after several weeks of administration. Interestingly, with PE-22-28, effects are produced within 4 days of administration only (3), which by far is the fastest known effective therapeutic agent.
Studies have shown that adults suffering from depression have a smaller volume of hippocampus in the brain. When treated with this compound, the smaller volume is reversed and is brought to optimal level, thereby combating depression. The reason behind this is believed to be the neurogenesis effect of the peptide, which is contributed by the cAMP signal cascade mechanism (6).
Pharmaceutical antidepressants are known to cause a wide range of side effects, including hallucinations, tremors, increased blood pressure and heart rate. This is primarily because most of the antidepressants not only inhibit TREK-1 receptors but other similar ones as well such as TREK-2, TRAAK, TRESK, etc.
Fortunately, studies (7) have proven that spadin and its derivatives, including PE-22-28, solely act on TREK-1 receptors and do not induce other side effects. Post three week administration, the peptide showed excellent antidepressant properties without inducing any seizures, glycemia and cardiac infarction.
Post Stroke Depression (PSD) Studies
Post Stroke Depression is a common neuropsychiatric disorder which is found in more than a quarter of stroke patients, especially in females (8). PSD mainly occurs due to over activity of the TREK-1 receptors.
A study (5) was conducted where the experimental mice, induced with PSD syndrome, were treated with either spadin peptide or SSRI (selective serotonin reuptake inhibitors) antidepressants. SSRI, as the name suggests, is a potent antidepressant that prevents the reabsorption of serotonin neurotransmitters.
While both medications prove to be potent, SSRIs induced a wide range of side effects while PE-22-28 peptide did not. What’s more, SSRI took longer to demonstrate the effects while the peptide was fast acting. Hence, the peptide proved to be highly effective against PSD, with possibly no known side effects.
Studies have shown that the peptide exerts neurogenesis (formation of neurons) and synaptogenesis (formation of synapse) both processes required for brain development.
Studies (9) were conducted both in vitro and in vivo where spadin derivatives were administered in the neuron cultures of mice tissues. In vitro administration led to MAPK and PI3K pathway activation, which led to neuron protection and formation. In vivo administration led to an increase in mRNA expression and concentration of brain derived neurotrophic factor (BDNF) in the hippocampus part of the brain.
Both studies proved that the peptide is effective in inducing neurogenesis that can thereby combat depression.
Besides depression, the hippocampus is critical for enhancing learning and memory. This is why it is understood that this region is also involved with other mental ailments like anxiety and Alzeihmer’s disease. Hence, studies suggest that peptide PE-22-28 also improves nootropic properties by improving the hippocampus region.
In Alzeihmer’s disease, there is a down regulation of CREB activity in the brain, i.e., cAMP response element binding activity. CREB is critical for growth and formation of neurons, which helps in memory development and neuronal plasticity. While it is believed that this compound will help reverse this down regulation and help combat Alzeihmer’s, studies are actively being conducted to investigate these effects of the peptide (10).
Improved Muscle Function Related Studies
Besides depression, TREK-1 receptor is known to affect the ability of muscles to respond to any outer stimulation. Upon stimulation, this receptor induces relaxation of the muscles, whereas blocking the receptors, it leads to a contraction of the muscles.
Based on this, PE-22-28 peptide is continuously being researched on to understand its potential effect on muscle relaxation and contraction, with a hope to potentially find a better treatment for conditions such as myogenic bladder dysfunction and lead to enhanced muscle performance (11).
Side Effects with PE-22-28 Peptide
PE-22-28 is a relatively safe peptide with very few to no side effects known so far. However, as with all other peptides, there may likely be minor side effects, including:
- Pain, redness and itchiness at the site of injection
- PE-22-28 has low oral bioavailability and is available for subcutaneous administration only
- Cough, fever, and flu like symptoms
- Joint pains
- May induce weight gain
Spadin, the natural peptide, has been known to scientists for a while now. Extensive research led to the formation of a spadin derivative known as PE-22-28 only recently in 2017. Since then all experimental studies, in mice and cell cultures, have yielded promising results in treating depression and other mental ailments.
There are no clinical trials available to date and thus FDA approval is still outstanding. This peptide is available for research purposes only, not for any human or therapeutic use yet.
PE-22-28 peptide is a short peptide composed of seven amino acids, which is a derivative of the endogenous protein called spadin. Owing to the short chain structure, the peptide is faster acting and has a longer half life than the natural protein.
There are several benefits of the compound over traditional existing antidepressants, including faster action, higher stability and minimal side effects.
Besides these benefits, PE-22-28 blocks the TREK-1 peptide, which causes increased excitability of neurons, thereby decreasing effects of depression. Furthermore, by selectively acting on the TREK-1 receptor, it does not exert any other side effects on the cardiac and nervous system.
Research has demonstrated that the peptide may also be useful in treating Alzheimer’s and improving muscle function. Preliminary research so far has shown promising results but further studies in humans continue to investigate the peptide properties.
1. Depression. https://medlineplus.gov/genetics/condition/depression/
2. Depression, World Health Organization. https://www.who.int/news-room/fact-sheets/detail/depression?msclkid=1b290e41ae0711ec8f12a9496f5f64ae
3. Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M. Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Front Pharmacol. 2017 Sep 12;8:643. https://pubmed.ncbi.nlm.nih.gov/28955242/
4. Mazella J, Pétrault O, Lucas G, Deval E, Béraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon JL, Heurteaux C, Borsotto M. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol. 2010 Apr 13;8(4):e1000355. https://pubmed.ncbi.nlm.nih.gov/20405001/
5. Djillani, A., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Frontiers in pharmacology, 10, 379. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470294/
6. Duman, R., Nakagawa, S. & Malberg, J. Regulation of Adult Neurogenesis by Antidepressant Treatment. Neuropsychopharmacol 25, 836–844 (2001). https://doi.org/10.1016/S0893-133X(01)00358-X
7. Moha Ou Maati H, Veyssiere J, Labbal F, Coppola T, Gandin C, Widmann C, Mazella J, Heurteaux C, Borsotto M. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology. 2012 Jan;62(1):278-88. https://pubmed.ncbi.nlm.nih.gov/21807005/
8. Post Stroke Depression. https://medical-dictionary.thefreedictionary.com/post-stroke+depression
9. Devader C, Khayachi A, Veyssière J, Moha Ou Maati H, Roulot M, Moreno S, Borsotto M, Martin S, Heurteaux C, Mazella J. In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. Br J Pharmacol. https://pubmed.ncbi.nlm.nih.gov/25598009/
10. Mental health: spadin, a fast-acting antidepressant. https://journals.biologists.com/dmm/article/3/7-8/398/2435/Mental-health-spadin-a-fast-acting-antidepressant
11. Lei Q, Pan XQ, Chang S, Malkowicz SB, Guzzo TJ, Malykhina AP. Response of the human detrusor to stretch is regulated by TREK-1, a two-pore-domain (K2P) mechano-gated potassium channel. J Physiol. 2014 Jul 15;592(14):3013-30. https://pubmed.ncbi.nlm.nih.gov/24801307
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