PE-22-28 is a synthetic derivative of the naturally occurring peptide spadin which binds to TREK-1.
TREK-1 is found in regions of the brain controlling mood, memory, and learning.
PE-22-28 is being researched for applications including antidepressant activity, learning, stroke recovery and neurodegenerative diseases such as Alzheimer’s.

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What is PE-22-28?

PE-22-28 is a synthetic derivative of the naturally occurring peptide spadin. Spadin is a secreted peptide derived from sortilin. It is an antagonist of the TREK-1 (TWIK-related-potassium channel) receptor, a two-pore potassium channel identified as a potential target in the treatment of depression and as a possible neurogenic regulator. Early studies in mice have shown that a deletion of the TREK-1 receptor makes them resistant to depression. Similarly, treatment with sortilin leads to resistance to depression boosts the growth of both neurons and the synaptic interconnections between neurons[1].

Interestingly, shortened analogs of spadin actually show better TREK-1 inhibition than spadin itself. PE-22-28 is the representative peptide for this group of synthetic spadin analogs. PE-22-28 has been shown to be more stable and have improved antidepressant activity and neurogenic properties over the naturally occurring spadin.

It is important to note that one of the long-term consequences of taking anti-depressant medications (e.g. SSRIs) is neurogenesis. In fact, the growth of new neurons is considered to be one indication that depression is being adequately treated and that antidepressants are working. PE-22-28 has been shown to induce neurogenesis after just 4 days, which is substantially faster than any known antidepressant. This also suggests that PE-22-28 might be useful in other applications such as learning, stroke recovery, and perhaps even the battle against neurodegenerative diseases[2].



Research in mouse models of depression indicates that PE-22-28 is more effective in reversing the symptoms of depression than any currently used treatment and that it does so with fewer side effects. In fact, PE-22-28 has been shown to relieve depression in just 4 days without producing any side effects on other functions that are controlled by the TREK-1 channel.

There is strong evidence to show that the hippocampus is smaller (of reduced volume) in patients suffering from depressive disorder and other affect disorders. Additionally, research has shown that long-term administration of classic antidepressants (5-HT or norepinephrine selective reuptake inhibitors) boosts neurogenesis in the adult rodent hippocampus and leads to increased hippocampus volume[4]. The ability of PE-22-28 to reverse this loss of volume by stimulating neurogenesis indicates that it is fighting depression at its source and that it may help to uncover some of the underlying physiologic pathways that are deficient in the setting of depression[5].

The lack of side effects caused by spadin and PE-22-28 is just as important as the effects of these peptides. Current treatments for depression have a host of known side effects ranging from suicidality to changes in libido and problems with cognition. In fact, side effects are the number one reason that people stop using their antidepressants and are reluctant to return to them even after their depression worsens. Even ketamine, which has been newly touted as a potential rapid-onset treatment for depression has a host of side effects including delirium, hallucinations, muscle tremors, high blood pressure, and increased heart rate. So, despite its rapid onset of action, doctors have been reluctant to use ketamine in the treatment of depression because of the range and severity of its side effects[6].

There was initial concern that spadin would also cause a host of side effects because the TREK-1 receptor has been implicated in pain sensitivity, seizure activity, and cardiac ischemia. There was also concern that spadin and PE-22-28 may inhibit currents in TREK-2, TRAAK, TASK, and TRESK channels leading additional side effects. Research in mice, however, shows that none of these side effects are observed and, in fact, PE-22-28 has one of the smallest side effect profiles of any existing or experimental treatment for depression[7].


Post-Stroke Depression

Post-stroke depression (PSD) is a common condition following brain ischemia and is particularly refractory to standard treatment. Recent research has shown that TREK-1 over-expression likely plays a causative role in this condition. In experimental mouse models, this upregulation can be suppressed or reversed using both SSRI antidepressants as well as TREK-1 blockers like spadin[3]. Of course, the SSRIs take much longer to act and have a host of side effects. This suggests that PE-22-28 may prove effective in future trials exploring the treatment of PSD.



The ability of antidepressant drugs to upregulate neurogenesis in the hippocampus has been well-established. Research with PE-22-28 shows that this peptide can perform the same function, but in a shorter duration of time. Studies in mice show that PE-22-28 increases both neurogenesis and synaptogenesis after just four days. Preliminary results indicate that PE-22-28 roughly doubles the amount of BrdU (an exogenous marker that is incorporated into DNA and used to detect replication) positive cells in the hippocampus.  In the case of synaptogenesis, PE-22-28 appears to double the rate of synapse formation[2], [8].

Another clue that PE-22-28 is boosting cell division in the brain is the increase in CREB seen after its administration. CREB (cAMP response element-binding protein) is a transcription factor associated with neuronal plasticity, memory formation, and the development of spatial memory. CREB appears to be a necessary component in not just the growth of neurons, but in their protection as well. Research in Alzheimer’s disease has shown a down-regulation of CREB and scientists have long sought a drug capable of boosting CREB as a means of treating Alzheimer’s[9], [10]. PE-22-28 is being actively investigated for its ability to both prevent and reverse the symptoms of Alzheimer’s disease.

The hippocampus, while playing an important role in depression, is also a critical structure for learning and memory. It is a very plastic structure that research has revealed to be vulnerable to damage by a variety of insults. The hippocampus has been implicated in diseases ranging from depression to anxiety to Alzheimer’s disease. Improving its ability to regenerate following injury could help to treat a number of diseases. Notably, the role of the hippocampus in learning, memory, and spatial navigation suggests that PE-22-28 or a similar TREK-1 antagonist may prove to be an effective nootropic.

Now, it has generally been demonstrated in animal models that removing the TREK-1 channel is a recipe for disaster. In previous mouse models, knockout of TREK-1 increased significantly the likelihood of seizure activity and reduced the normal ability of this two-pore potassium channel to protect neurons from excitotoxicity. It came as a bit of surprise then that neither spadin nor PE-22-28 enhanced seizure activity. Even more interesting is the fact that mice treated with spadin are more resistant to developing generalized seizures[3]. PE-22-28 has even more profound protective effects than spadin.




Top: Number of cells in the hippocampus of mice treated with saline, fluoxetine (Prozac), and spadin for four days.

Middle: Quantification of CREB activity in the brain of mice treated with saline and spadin.

Bottom: Effect of spadin on the firing rate of 5-HT neurons (neurons implicated in depression) at baseline (WT), in TREK-1 knockout mice (KO), and after administration of spadin and saline. Note that spadin boosts firing in neurons almost as much as removing TREK-1 entirely.


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