PE-22-28 is a 7-amino-acid peptide derived from the degradation products of spadin (PE 12-28), which itself originates from the post-translational maturation of sortilin. Researchers have posited that the peptide may act primarily through a TREK-1 blockade, and data collected from in vitro cellular samples suggest it may do so with considerably greater affinity than its parent peptide spadin.

TREK-1 is a two-pore domain potassium channel involved in stabilizing membrane potential and dampening neuronal excitability, possibly linked to better-supported serotonergic neurotransmission. Beyond channel interaction, PE-22-28 may additionally engage neuroplasticity pathways, such as promoting neurogenesis and synaptogenesis.

PE-22-28 Peptide and TREK-1 Inhibition

The primary potential  mechanism of action of PE-22–28 peptide is considered by researchers to be exerted via blocking the TREK-1 channels in the central nervous system. According to Djillani et al., PE-22–28 is “the shortest, most efficient sequence capable of blocking the TREK-1 channel with higher potency” than spadin.^[2] TREK-1 is generally the most studied background two-pore domain potassium channel. Its main role is considered to be controling cell excitability and maintaining the membrane potential below the threshold of depolarization.^[3] TREK-1 may also be multi-regulated by a variety of physical and chemical stimuli. TREK-1 has also been reported in the heart and several other organs, but inhibition of these channels has unknown impact.^[4]

By blocking TREK-1, murine studies suggest that PE-22–28 may significantly decrease immobility time in the forced swim test (FST) compared to control mice that received saline.^[1] The FST is a common test used to measure depressive behavior in rodents, where the mice are placed in a water tank, and their mobility is monitored. In addition, the study also evaluated the potential of PE-22–28 on the learned helplessness test (LHT), another test with similar indications as FST. The LHT measures the time it takes for mice to escape from an aversive stimulus. The study commented that the sub-chronic presentation of PE-22–28 appears to significantly reduce the escape latencies in the LHT.

Furthermore, the trial evaluated the potential of PE-22-28 on a mice model of long-term corticosterone presentation.^[1] Corticosterone is a hormone that is involved in the body’s response to stress, and chronic exposure to high levels of corticosterone has been associated with depressive behavior in rodents. The results of this study suggested that PE-22–28 peptide may result in decreasing immobility time in the FST. It may also reduce the latency to eat in the novelty-suppressed feeding (NSF) test, which measures an animal’s willingness to eat in a stressful environment.

PE-22-28 Peptide and Serotonin Transmission

Researchers posit that PE-22–28 may inhibit TREK-1, possibly leading to the excitation of the dorsal raphé nucleus and the firing of serotonin transmission.^[5] The researchers suggest that “if a viral vector that leads to the secretion of PE 22-28 is [presented to] the dorsal raphé nucleus, the peptide will block the channel and thereby activate the serotonergic neurons, resulting in the facilitation of serotonergic transmission, as SSRIs do.”

Studies suggest that PE-22–28 peptide may act as a blocker of the TREK-1 channel, similar to spadin, and Maati et al. investigated these actions in relation to the connectivity between the medial prefrontal cortex (mPFC) and dorsal raphé serotonergic neurons.^[6] The study commented that spadin might increase the firing rate of serotonin neurons and that the action of spadin and 5-HT4 agonists appeared additive and independent of each other. However, adding a mGluR2/3 antagonist reportedly blocked the action of spadin, suggesting that spadin likely depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors. Therefore, the researchers further suggested that PE-22-28 may also interact with the mGluR2/3 receptors, similar to spadin, to fire up the serotonin neurons.

The mGluR2/3 is a metabotropic glutamate receptor found in the central nervous system. They are G protein-coupled receptors that are considered to be activated by the neurotransmitter glutamate. There are two subtypes of mGluR2/3 receptors: mGluR2 and mGluR3, and they are both involved in regulating neurotransmitter release.^[7] Activation of mGluR2/3 receptors appears to inhibit the release of glutamate and other neurotransmitters, such as GABA and dopamine. This mechanism may help to regulate synaptic transmission and maintain the balance of excitatory and inhibitory neurotransmission in the brain. The study also suggested that the combination of 5-HT activators should be cautiously approached.^[6]

PE-22-28 Peptide and Neuroplasticity

One in vitro trial suggested that inhibiting TREK-1 may increase neuronal membrane potential and activate both MAPK and PI3K signaling pathways in a time- and concentration-dependent manner.^[8] The latter pathway has been linked to the supposed protective action of spadin against apoptosis. Inhibiting TREK-1 also appeared to enhance mRNA expression and protein levels of two markers of synaptogenesis, PSD-95, and synapsin. Inhibiting TREK-1 may increase the proportion of mature spines in cortical neurons, suggesting increased neuroplasticity. Inhibiting TREK-1 appeared in other experimental models to increase mRNA expression and protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, suggesting a neuroplasticity potential.^[8]

In one murine model, PE-22-28 was presented for 4 days, and on the 5th day, the brains of the rats were analyzed.^[1] The results suggested that PE-22-28 significantly increased the number of bromodeoxyuridine (BrdU) positive cells in the hippocampus compared with saline mice, suggesting that PE-22-28 may induce hippocampal neurogenesis similar to spadin. BrdU is a thymidine analog that incorporates the DNA of dividing cells during the S-phase of the cell cycle.