Peptides > PE-22-28


PE-22-28 is a synthetic derivative of the naturally occurring peptide spadin, and it has an affinity for binding to TREK-1, a protein found in brain regions responsible for regulating mood, memory, and learning. Research on PE-22-28 is underway, exploring its potential applications, which include antidepressant effects, enhancement of learning processes, facilitation of stroke recovery, and its role in addressing neurodegenerative conditions like Alzheimer’s disease.

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1. What is PE-22-28?


2. PE-22-28 Peptide Structure


3. PE-22-28 Research

What is PE-22-28?

PE-22-28 is a synthetic derivative of the naturally occurring peptide spadin. Spadin is derived from sortilin and acts as an antagonist to the TREK-1 (TWIK-related-potassium channel) receptor, a two-pore potassium channel that has been identified as a potential target for the treatment of depression and a potential regulator of neurogenesis. Early studies involving mice have revealed that the removal of the TREK-1 receptor makes them resistant to depression. Additionally, treatment with sortilin has been shown to induce resistance to depression while promoting the growth of both neurons and synaptic connections between neurons.

What’s particularly intriguing is that shortened analogs of spadin have exhibited even better TREK-1 inhibition than the natural spadin itself. Among these synthetic spadin analogs, PE-22-28 stands out as a representative peptide. PE-22-28 has demonstrated increased stability and improved antidepressant and neurogenic properties compared to naturally occurring spadin.

It’s worth noting that one of the long-term effects of taking antidepressant medications, such as SSRIs, is the promotion of neurogenesis. The growth of new neurons is considered an indicator that depression is being effectively treated and that antidepressants are effective. PE-22-28 has been shown to induce neurogenesis in as little as four days, a significantly faster timeline than any known antidepressant. This suggests that PE-22-28 may have potential applications in areas beyond depression treatment, such as enhancing learning, aiding in stroke recovery, and possibly even addressing neurodegenerative diseases.

While TREK-1 is predominantly found in the brain, it is also present in other body tissues, including the heart, smooth muscle cells, lung tissue, the prostate, and specific regions of the pancreas. Although its primary focus has been on its potential as a target for antidepressant activity, TREK-1 plays essential roles in pain perception, anesthesia, and neuroprotection. These diverse properties have positioned TREK-1 as a significant research target in both academic and industry settings.

PE-22-28 Peptide Structure

Molecular Formula: C96H142N26O22
Molecular Weight: 2012.3492 g/mol

PE-22-28 Sequence: GVSWGLR
Molecular Formula: C35H55N11O9
Molecular Weight: 773.8947 g/mol

PE-22-28 Research

Understanding TREK-1: A Key Potassium Channel in Neurons TREK-1, also known as TWIK-related K+ channel 1, is a two-pore potassium channel that plays a vital role in regulating the excitability of neurons. It is part of a larger family of two-pore potassium channels, each of which contributes to the intricate control of neuronal function. TREK-1, specifically, is prominently found in specific brain regions associated with mood regulation, memory, and learning. These regions encompass the prefrontal cortex, the amygdala, and the hippocampus.

PE-22-28: A Potential Breakthrough in Depression Treatment Research conducted in mouse models of depression has revealed that PE-22-28 holds remarkable efficacy in alleviating depression symptoms, surpassing the effectiveness of currently employed treatments while exhibiting fewer side effects. Notably, PE-22-28 has demonstrated the capacity to relieve depression in just four days without affecting other functions regulated by the TREK-1 channel.

Depression is often associated with a reduced volume of the hippocampus, a critical brain region. Long-term use of conventional antidepressants has been shown to promote neurogenesis in the hippocampus, resulting in increased hippocampal volume. PE-22-28’s ability to stimulate neurogenesis and reverse this volume loss suggests that it addresses depression at its core and may help unveil some of the underlying physiological pathways involved in depression.

The lack of side effects associated with spadin and PE-22-28 is of paramount importance. Current depression treatments are notorious for their array of side effects, ranging from suicidal tendencies to altered libido and cognitive impairments. Even ketamine, which has gained attention as a rapid-onset depression treatment, comes with a host of side effects, including delirium, hallucinations, muscle tremors, high blood pressure, and increased heart rate. Consequently, the utilization of ketamine for depression treatment has been met with hesitation due to the severity and diversity of its side effects.

Initially, concerns were raised about potential side effects of spadin and PE-22-28, as the TREK-1 receptor has been implicated in pain sensitivity, seizure activity, and cardiac ischemia. Moreover, there were apprehensions about whether spadin and PE-22-28 might inhibit currents in other potassium channels like TREK-2, TRAAK, TASK, and TRESK, leading to additional side effects. However, research in mice has demonstrated the absence of these side effects, with PE-22-28 exhibiting one of the most minimal side effect profiles among existing and experimental depression treatments.

Addressing Post-Stroke Depression (PSD) Post-stroke depression (PSD) often follows brain ischemia and proves challenging to treat using standard methods. Recent research suggests that overexpression of TREK-1 contributes to PSD. In mouse models, this upregulation can be mitigated or reversed using selective serotonin reuptake inhibitors (SSRIs) and TREK-1 blockers like spadin. Notably, SSRIs take significantly longer to exert their effects and are associated with a variety of side effects. This implies that PE-22-28 may hold promise as a potential treatment for PSD in future trials.

Neurogenesis Enhancement Antidepressant drugs are known for their capacity to stimulate neurogenesis in the hippocampus. Research has shown that PE-22-28 can achieve a similar outcome but in a much shorter timeframe. Studies in mice indicate that after just four days of PE-22-28 administration, both neurogenesis and synaptogenesis are significantly increased. Preliminary data suggests that PE-22-28 approximately doubles the number of BrdU-positive cells in the hippocampus. Furthermore, it appears to double the rate of synapse formation.

A potential clue to PE-22-28’s impact on brain cell division lies in its ability to elevate CREB levels. CREB (cAMP response element-binding protein) is a transcription factor linked to neuronal plasticity, memory formation, and spatial memory development. Notably, CREB has been implicated in neuronal growth and protection, particularly in the context of Alzheimer’s disease. PE-22-28 is actively under investigation for its potential to prevent and reverse Alzheimer’s symptoms.

The hippocampus, in addition to its role in depression, is crucial for learning, memory, and spatial navigation. This plastic brain structure is vulnerable to damage from various insults, and enhancing its regenerative abilities could hold promise in treating multiple diseases. Notably, the hippocampus’s involvement in cognition suggests that PE-22-28 or a similar TREK-1 antagonist may have potential as a nootropic.

While removing the TREK-1 channel in animal models has been linked to detrimental consequences such as increased seizure activity and reduced neuroprotective effects, spadin and PE-22-28 do not exacerbate seizure activity. In fact, mice treated with spadin exhibit increased resistance to generalized seizures. PE-22-28 demonstrates even more substantial protective effects compared to spadin.

TREK-1 and Its Role in Muscle Function Preliminary research suggests that TREK-1 plays a pivotal role in muscle response to mechanical stimulation. Specifically, blocking TREK-1 appears to enhance muscle contractility, while channel activation promotes muscle relaxation. Although this aspect of the TREK-1 channel is still in its early stages of investigation, its significance is growing. There is optimism that comprehending the function of molecules like PE-22-28 in muscle contraction and relaxation may not only lead to new treatment strategies for conditions like myogenic bladder dysfunction but also offer insights into the physiology of muscle performance[^11^].

In Summary Dr. Jean Mazella, one of the lead researchers behind the development of PE-22-28, has designed the peptide with the specific goal of advancing the use of spadin analogs in clinical applications. PE-22-28 demonstrates effectiveness as a depression treatment and serves as a potent stimulator of neurogenesis and synaptogenesis in the hippocampus. Its remarkable attribute is its minimal side effects when compared to existing antidepressant medications. Furthermore, it appears to maintain its ability to antagonize TREK-1 even after modifications that extend its half-life or change the route of administration. In essence, PE-22-28 presents a promising target for guiding the development of a new generation of antidepressants and contributes to the evolving field of nootropics. Additionally, it aids in expanding the arsenal of drugs employed in the treatment of neurodegenerative disorders like Alzheimer’s disease.

Article Author

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.


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