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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. Similarmente, treatment with sortilin leads to resistance to depression boosts the growth of both neurons and the synaptic interconnections between neurons[1].
Curiosamente, 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 (p.ej. ISRS) is neurogenesis. De hecho, 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 días, 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].
TREK-1, which is primarily found in the brain, is also found in the heart, smooth muscle cells, lung tissue, the prostate, and in specific areas of the pancreas. Though it has been primarily studied as a target for antidepressant activity, TREK-1 plays important roles in pain perception, anesthesia, and neuroprotection. These properties have made TREK-1 a major research target in academia and industry.
Estructuras
Spadin Sequence: YAPLPRWSGPIGVSWGLR
Fórmula molecular: C96h142norte26oh22
Peso molecular: 2012.3492 g/mol
PE-22-28 Sequence: GVSWGLR
Fórmula molecular: C35h55norte11oh9
Peso molecular: 773.8947 g/mol
Fuente: PubChem
PE-22-28 Research
What Is TREK-1?
The receptor that spadin and thus PE-22-28 primarily bind to is TREK-1. TREK-1 is a two-pore potassium channel regulated by a number of different molecules. It belongs to a large family of two-pore potassium channels that are important in regulating the excitability of neurons. TREK-1, En particular, is found in regions of the brain controlling mood, memoria, and learning. These areas include the prefrontal cortex, the amygdala, and the hippocampus. Stimulating TREK-1 activity reduces excitability of the neuron while reducing TREK-1 function increases excitability and increases the likelihood of a depolarization event[3]. By reducing excitability of the neuron, TREK-1 can help to protect against excitotoxicity.
Fuente: PubMed
Depression
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. De hecho, 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. Además, 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. De hecho, 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, hipertensión, and increased heart rate. Entonces, 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, sin embargo, shows that none of these side effects are observed and, En realidad, 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]. Por supuesto, 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.
Neurogenesis
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, memoria, and spatial navigation suggests that PE-22-28 or a similar TREK-1 antagonist may prove to be an effective nootropic.
Ahora, 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.
Fuente: OCL – Oilseeds and fats, Crops and Lipid
Muscle Function
There is some research to suggest that TREK-1 plays an important role in the ability of muscle to respond to mechanical stimulation. En particular, TREK-1 blockade appears to increase contractility in muscle tissue while activation of the channel appears to promote muscle relaxation. While this particular aspect of the TREK-1 channel is still in the early stages of investigation, it is becoming increasingly important. There is hope that understanding the role of molecules like PE-22-28 in muscle contraction and relaxation may not only provide new treatment modalities for conditions like myogenic bladder dysfunction, but may also open up new pathways for understanding the physiology of muscle performance[11].
Resumen
Según la Dra.. Jean Mazella, one of the lead researchers in the development of PE-22-28, the peptide was specifically designed to move forward the use of spadin analogs in clinics. PE-22-28 appears to be an effective treatment for depression and a potent stimulator of neurogenesis and synaptogenesis in the hippocampus. It has far fewer side effects than existing antidepressant medications and appears to retain much of its ability to antagonize TREK-1 even after modifications that boost half-life or alter the route of administration. En breve, PE-22-28 appears to offer a strong target for guiding the development of a new generation of antidepressants and is helping to shed light on the burgeoning field of nootropics. It is also helping to expand the arsenal of drugs used to treat neurodegenerative diseases like Alzheimer’s disease.
Autor del artículo
La literatura anterior fue investigada, editado y organizado por el Dr.. mi. logan, MARYLAND. Dr. mi. Logan tiene un doctorado de Facultad de Medicina de la Universidad Case Western Reserve y una licenciatura. en biología molecular.
Autor de revista científica
Dr. Jean Mazella obtained his PhD in 1984 from the University of Nice, Francia, and fulfilled the role of Assistant Professor at the Montreal Neurological Institute, Canada, from 1994-95. He is currently leading the ‘Cellular Biology of Neuropeptides and Associated Pathologies’ project at the Institute of Molecular and Cellular Pharmacology (IPMC) in France, and is Coordinator for ANR’s ENCOD (2012-14) and MEDINCOD (2014-17) programmes. His pioneering research about Spadins and the subsequent analog PE-22-28 seems to partly originate from him investigating the Sortilin/neurotensin receptor-3 system that, once knocked-out, exhibited similar effects to Spadin and PE-22-28 peptides like reduced fibrosis and higher 5-HT firing rate.
Dr. Jean Mazella is being referenced as one of the leading scientists involved in the research and development of PE-22-28. De ninguna manera este médico/científico respalda o defiende la compra, venta, o uso de este producto por cualquier motivo. No hay afiliación o relación., implícito o no, entre
Citas referenciadas
- j. Mazella et al., “Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design," PLoS Biol., volumen. 8, No. 4, pag. e1000355, Abr. 2010, doi: 10.1371/journal.pbio.1000355.
- A. Djillani, METRO. Pietri, S. Moreno, C. Heurteaux, j. Mazella, y M. Borsotto, “Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity," Frente. farmacología., volumen. 8, Sep. 2017, doi: 10.3389/fphar.2017.00643.
- A. Djillani, j. Mazella, C. Heurteaux, y M. Borsotto, “Role of TREK-1 in Health and Disease, Focus on the Central Nervous System," Frente. farmacología., volumen. 10, Abr. 2019, doi: 10.3389/fphar.2019.00379.
- R. S. Duman, S. Nakagawa, y j. Malberg, “Regulation of adult neurogenesis by antidepressant treatment," Neuropsicofarmacol. Apagado. público. Soy. Coll. Neuropsicofarmacol., volumen. 25, No. 6, páginas. 836–844, Dic. 2001, doi: 10.1016/S0893-133X(01)00358-incógnita.
- j. mi. Malberg and L. mi. Schechter, “Increasing hippocampal neurogenesis: a novel mechanism for antidepressant drugs," actual. farmacia. Del., volumen. 11, No. 2, páginas. 145–155, 2005, doi: 10.2174/1381612053382223.
- norte. Katalinic, R. Lai, A. Somogyi, PAG. B. Mitchell, PAG. Glue, y C. k. Loo, “Ketamine as a new treatment for depression: a review of its efficacy and adverse effects," Aust. norte. z. j. Psiquiatría, volumen. 47, No. 8, páginas. 710–727, Ago. 2013, doi: 10.1177/0004867413486842.
- h. Moha Ou Maati et al., “Spadin as a new antidepressant: absence of TREK-1-related side effects," Neuropharmacology, volumen. 62, No. 1, páginas. 278–288, Ene. 2012, doi: 10.1016/j.neuropharm.2011.07.019.
- C. Devader et al., “In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin," hermano. j. farmacología., volumen. 172, No. 10, páginas. 2604–2617, Puede 2015, doi: 10.1111/bph.13083.
- A. j. Silva, j. h. Kogan, PAG. W.. Frankland, y S. Kida, “CREB and memory," Annu. Rdo. neurociencias., volumen. 21, páginas. 127–148, 1998, doi: 10.1146/annurev.neuro.21.1.127.
- t. C. of B. Limited, “Mental health: spadin, a fast-acting antidepressant," dis. Model. Mech., volumen. 3, No. 7–8, páginas. 398–398, Jul. 2010.
- q. Lei, X.-Q. Pan, S. Chang, S. B. Malkowicz, t. j. Guzzo, y un. PAG. Malykhina, “Response of the human detrusor to stretch is regulated by TREK-1, a two-pore-domain (K2P) mechano-gated potassium channel," j. fisiol., volumen. 592, No. 14, páginas. 3013–3030, Jul. 2014, doi: 10.1113/jphysiol.2014.271718.
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