Serotonin Transmission and PE-22-28 Research

Spadin is a protein found naturally in the brain, and its synthetic analog, PE-22-28, has been hypothesized to have similar properties. The amino acid sequence used to create PE-22-28 is based on the 22nd to the 28th amino acids of the spadin protein. PE-22-28 has the following amino acid sequence: Proline, Glutamine, Glycine, Aspartic acid, Asparagine, Cysteine, Cysteine, and the two cysteine residues may help to stabilize the molecule by generating a disulfide link.

A short but potentially powerful spadin analog was originally synthesized in 2017 by Djillani et al. PE-22-28 seems to interact with many CNS ion channels, including the two-pore domain potassium channel TREK-1 (TWIK-related K+ channel 1), suggesting that it may have a role similar to that of spadin. In addition to the pancreas, lungs, kidneys, heart, and muscles, TREK-1 is present in the brain.

In addition to its potential function in pain perception, mood control, and neuroprotection, TREK-1 is thought by scientists to be broadly expressed in the central nervous system. Research suggests that PE-22-28 may attach to the TREK-1 channel’s extracellular domain and suppress the channel’s activity. Understanding the mechanisms of action and possible impacts of PE-22-28 will need more study. Other analogs with modified N- and C-termini have also been designed using PE 22-28 as the core peptide.

PE-22-28 Peptide and TREK-1 

Researchers speculate that inhibiting TREK-1 channels in the central nervous system may be the key possible mechanism of action of PE-22-28. PE-22-28 is “the shortest, most efficient succession capable of stopping the TREK-1 channel with higher potency” than spadin, as suggested by Djillani et al. As far as two-pore domain potassium channels go, TREK-1 has been the subject of the greatest research. The regulation of cellular excitability and the prevention of membrane depolarization are speculated to be its primary functions. Physical and chemical cues may both play a role in regulating TREK-1. Heart and other organ TREK-1 reports have been made; however, the effects of blocking these channels are unclear.

In the forced swim test (FST), PE-22-28 has been suggested to dramatically reduce immobility time in mouse models by inhibiting TREK-1 compared to saline-treated controls. Mice are often put in a water tank, and their activity levels are measured as part of the FST, which assesses depression in animals. The prospect of PE-22-28 on the learned helplessness test (LHT), a test with comparable indications as the FST, was also assessed in this research. Mice’s reaction times to unpleasant stimuli are quantified using the LHT. Sub-chronic presentation of PE-22-28 was suggested to shorten LHT escape latencies considerably, as suggested by the research.

In addition, the experiment assessed the PE-22-28 peptide’s potential in a mouse model of chronic corticosterone presentation. Chronic exposure to high amounts of corticosterone has been linked to depressed behavior in mice. Corticosterone is a hormone involved in the biological reaction to stress. This study’s findings purported that PE-22-28 might lead to less time spent sitting throughout the FST. In the novelty-suppressed feeding (NSF) test, which evaluates an animal’s readiness to eat under stress, it may also shorten the latency to eat.

PE-22-28 Peptide and Serotonin Transmission 

Serotonin transmission might be triggered, and the dorsal raphé nucleus excited if PE-22-28 blocks TREK-1, as hypothesized by the study’s authors. Scientists speculate that “if a viral vector that leads to the release of PE 22-28 is [given to] the dorsal raphé nucleus, the peptide will preclude the channel and thereby trigger the serotonergic neurons, ending in the facilitation of serotonergic transmission, as SSRIs do.”

Maati et al. examined the relationship between the medial prefrontal cortex (mPFC) and dorsal raphé serotonergic neurons. They found data suggesting that PE-22-28 may operate as a blocker of the TREK-1 channel, like spadin. The research authors proposed that spadin’s activity was additive and independent of that of 5-HT4 agonists and that this may boost the firing rate of serotonin neurons. The addition of a mGluR2/3 antagonist, however, was suggested to inhibit spadin’s activity, indicating that spadin probably relies on mPFC TREK-1 channels connected to mGluR2/3 receptors. Researchers implied that PE-22-28, like spadin, may stimulate serotonin neurons by interacting with the mGluR2/3 receptors.

PE-22-28 Peptide and Synaptic Plasticity 

One in vitro study suggested that blocking TREK-1 led to a time- and concentration-dependent rise in neuronal membrane potential and activation of MAPK and PI3K signaling pathways. Data suggests that spadin may protect cells from apoptosis via the second route. Both PSD-95 (a diagnostic of synaptogenesis) and synapsin (a sign of completed synapses) suggested increased mRNA expression and protein levels after TREK-1 inhibition. Neurons in the cortex may show more neuroplasticity if TREK-1 is inhibited, leading to a higher percentage of mature spines. It has been suggested in different animal models that blocking TREK-1 raises brain-derived neurotrophic factor (BDNF) mRNA expression and protein grades in the hippocampus, indicating neuroplasticity potential.

The brains of rats were examined after being exposed to PE-22-28 in a murine model for four days. Compared to saline-exposed animals, the number of bromodeoxyuridine (BrdU)-positive cells in the hippocampus appeared considerably higher in mice presented with PE-22-28, suggesting that this compound, like spadin, may trigger hippocampal neurogenesis. During the S-phase of the cell cycle, BrdU, a thymidine analog, is integrated into the DNA of dividing cells.

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[i] Djillani, A., Pietri, M., Moreno, S., Heurteaux, C., Mazella, J., & Borsotto, M. (2017). Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Frontiers in pharmacology, 8, 643.

[ii] Djillani, A., Pietri, M., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacology & therapeutics, 194, 185–198.

[iii] 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.

[iv] Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, Lazdunski M. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 1996 Dec 16;15(24):6854-62. PMID: 9003761; PMCID: PMC452511.

[v] Okada, M., & Ortiz, E. (2022). Viral vector-mediated expressions of venom peptides as novel gene therapy for anxiety and depression. Medical Hypotheses, 166, 110910.

[vi] Moha ou Maati, H., Bourcier-Lucas, C., Veyssiere, J., Kanzari, A., Heurteaux, C., Borsotto, M., Haddjeri, N., & Lucas, G. (2016). The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function. Brain structure & function, 221(1), 21–37.

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