For several years, scientists have been interested in the TREK-1 protein, which could be a breakthrough in the treatment of depression. is a basic potassium channel regulated by various neurotransmitters, including 5-HT.TREK ion channels (KCNK2) belong to a large family of K+ type K2P channels with a similar structure. These channels are composed of two domains, each consisting of four transmembrane segments .Channels of the TREK subfamily are commonly found in many areas of the central and peripheral nervous system. Their presence has been demonstrated in GABA-ergic interneurons of the caudate nucleus and shell, prefrontal cortex, hippocampus, hypothalamus, serotonergic neurons of the dorsal sutural nucleus and sensory neurons of the spinal ganglia, among others .
In one study by Heurteaux et al. (2004) used mice lacking the TREK1 gene (knockout, TREK-/- mice). In behavioral studies, it has been observed that these animals are characterized by resistance to typical stimuli that induce depressive states (depression-resistant phenotype ). In commonly used laboratory models of depression, such as the tail suspension test and forced swim test, mice lacking the gene behaved similarly to normal genotype(wild-type) animals successfully treated withselective serotoninreuptake inhibitors (SSRIs). Administration of SSRIs to TREK-/- mice did not cause further behavioral changes. In addition, the “depression resistance” of mice lacking the TREK-/- gene was reduced when the animals were given a tryptophan hydroxylase inhibitor, which reduces serotonin levels at synaptic terminals.
There is already early evidence of links between TREK-1 channels and depression in humans. In the study by Liou et al. (2009) assessed the polymorphism of the KCNK2 gene (encoding the TREK-1 channel) in depressed and control subjects . A statistically significant association of one of the gene variants with a significantly higher susceptibility to depression and a positive response to antidepressant treatment was demonstrated.
An interesting TREK-1 blocker is spadin, a natural peptide isolated from a propeptide secreted during the maturation of the neurotensin 3 receptor with the strongest selective TREK-1 channel-blocking activity to date. The antidepressant effect of spadine was evaluated on an animal model by biochemical, electrophysiological and behavioral methods in the study by Mazella et al. (2010) . The results showed that spadin, by stimulating the activity of neurons in the dorsal sutural nucleus, contributes to a significant increase in serotonergic neurotransmission. What’s more, spadyne-treated mice developed a depression-resistant phenotype (such as in TREK-1-/- mice) in less time compared to treatment with classical SSRIs. Intravenous administration of spadin intensified the processes of neurogenesis in the hippocampi, which are considered crucial to the effectiveness of chronic SSRI treatment. In studies to date, no clinically significant adverse effects potentially related to blockade of TREK-1 channels in the peripheral nervous system and other excitable cells (e.g., cardiac arrhythmias, blood pressure fluctuations) have been observed in experimental animals. An important limitation was the use of these compounds in humans by Intravenous or cerebrospinal fluid administration and short duration of action.
Spadyna is able to counteract depression in as little as 4 days and in that time induces neurogenesis, when classic antidepressants require 3-4 weeks to be effective. Nevertheless, Spadyne is poorly stable and only works for 7h, so scientists came up with the idea to convert Spadyne. Alaeddine Djillani et al. (2019) examined Spadin analogs, including PE 22-28, which interestingly showed a much longer duration of action (24 hours) and was more stable and potent in blocking TREK-1.
PE-22-28 [Gly-Val-Ser-Trp-Gly-Leu-Arg] is a 7 amino acid analogue of Spadin , which acts much stronger and longer, and thus induces neurogenesis in a few days. It was created by Retro-inverso synthesis ( I wrote about this method apropo Foxo4-DRI).Very often the properties of retro-inverso peptides are the same or similar, sometimes even better, than the parent peptides, and have greater resistance to proteolysis. Retro-inverso changes not only the chirality of the amino acids, but also the sequence is reversed.
-Supportive for depression
-Acts much faster than antidepressants
-Induces neurogenesis after just a few days
-Helps with post-traumatic depression
-Shows better specificity and affinity for the trek channel than Spadyna
-No side effects
-Invivo, daily administration of spadin for 4 days increased mRNA expression of BDNF, PSD-95 and synapsin after just 7 days in the hippocampus.
-Increased synaptogenesis (doubles the rate of synapse formation)
-Helps fight neurodegenerative diseases
-Helping you recover from a stroke
-Increases levels of CERB, which is a transcription factor associated with neuronal plasticity, memory formation and spatial memory development