Selank: Mechanism of Action
Mechanism of Action
Dual Mechanism: GABA-A Modulation + Enkephalinase Inhibition
Selank possesses a unique dual mechanism of action distinguishing it from classical anxiolytics:
1. GABA-A Receptor Positive Allosteric Modulation
Selank acts as a positive allosteric modulator (PAM) of the GABA-A receptor. Its binding site is distinct from the classical benzodiazepine site, though partial overlap may exist.[8] This modulation enhances the affinity of the receptor for GABA, increasing inhibitory neurotransmission without producing sedation, amnesia, or muscle relaxation.[5]
Selank administration significantly alters mRNA levels of GABA receptor subunits — Gabrb3, Gabre (epsilon), and Gabrq (theta) — as well as the GABA transporter Slc6a13 (GAT-2) in the frontal cortex. Dramatically, Gabre and Gabrq decreased approximately 20-fold at 1 hour, while Hcrt (orexin/hypocretin) decreased 25-fold then surged 128-fold by 3 hours.[9] This orexin rebound is hypothesized to explain the absence of sedation typical of benzodiazepines.
2. Enkephalinase Inhibition
Selank competitively inhibits enzymes responsible for the degradation of enkephalins (endogenous opioid peptides), including aminopeptidases, carboxypeptidase H, and angiotensin-converting enzyme (ACE). The inhibitory effect has an IC50 of approximately 15–20 μM in human serum assays.[10] This extends the half-life of Leu-enkephalin, potentiating the body's natural stress-limiting and analgesic pathways.[11]
BDNF/TrkB Signaling
Selank rapidly elevates expression of Brain-Derived Neurotrophic Factor (BDNF) and its receptor TrkB. An increase in Bdnf mRNA is observed in the hippocampus as early as 90 minutes, with protein levels increasing by 24 hours.[12]
Monoamine Neurotransmitter Modulation
Selank induces region-specific changes in monoamine metabolism:
- Serotonin: Increased 5-HIAA (metabolite) in hypothalamus and brainstem within 30 minutes to 2 hours[13]
- Norepinephrine: Increased in the hypothalamus[13]
- Dopamine: Strain-dependent — decreased metabolites in high-anxiety (BALB/c) mice, increased in low-anxiety (C57BL/6) mice[13]
Immunomodulation
Selank modulates IL-6 expression, normalizes the Th1/Th2 cytokine balance, and induces interferon-alpha (IFN-α) secretion.[14]
Receptor Selectivity
Importantly, radioreceptor assays show that Selank does not directly displace ligands from benzodiazepine, dopamine (D2), serotonin (5-HT2), or opioid (μ, δ) receptors. Its effects on these systems are downstream or allosteric.[8] However, the opioid antagonist naloxone blocks Selank's anxiolytic effects, confirming the enkephalin system's involvement.[15]
References
- Kolomin TA, Shadrina M, Slominsky P, Limborska SA, Myasoedov NF. A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides. Neuroscience & Medicine. 2013;4(4):223–252.
- Vyunova TV, Andreeva LA, Shevchenko KV, Myasoedov NF. Peptide-based Anxiolytics: The Molecular Aspects of Heptapeptide Selank Biological Activity. Protein & Peptide Letters. 2018;25(10):914–923.
- Medvedev VE, Tereshchenko ON, Kost NV, et al. Optimization of the treatment of anxiety disorders with selank. Zhurnal Nevrologii i Psikhiatrii. 2015;115(6):33–40.
- U.S. Food and Drug Administration. Bulk Drug Substances Used in Compounding Under Section 503B. FDA Compounding Database. 2023.
- Zozulya AA, Neznamov GG, Syunyakov TS, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zhurnal Nevropatologii i Psikhiatrii. 2008;108(4):38–48.
- Kozlovskii II, Danchev ND. The optimizing action of the synthetic peptide Selank on a conditioned active avoidance reflex in rats. Neuroscience and Behavioral Physiology. 2003;33(7):639–643.
- Kolomin TA, Agapova T, Agniullin YV, et al. Changes in the Transcription Profile of the Hippocampus in Response to Administration of the Tuftsin Analog Selank. Neuroscience and Behavioral Physiology. 2014;44(8):849–855.
- V'yunova TV, Andreeva LA, Shevchenko KV, et al. Peptide regulation of specific ligand-receptor interactions of GABA with the plasma membranes of nerve cells. Neurochemical Journal. 2014;8(4):259–264.
- Volkova A, Shadrina M, Kolomin T, et al. Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission. Frontiers in Pharmacology. 2016;7:31.
- Kost NV, Sokolov OY, Gabaeva MV, et al. Semax and Selank Inhibit the Enkephalin-Degrading Enzymes of Human Serum. Russian Journal of Bioorganic Chemistry. 2001;27(3):180–183.
- Zozulya AA, Kost NV, Sokolov OY, et al. The Inhibitory Effect of Selank on Enkephalin-Degrading Enzymes as a Possible Mechanism of Its Anxiolytic Activity. Bull Exp Biol Med. 2001;131(4):315–317.
- Inozemtseva LS, Karpenko EA, Dolotov OV, et al. Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo. Doklady Biological Sciences. 2008;421:241–243.
- Narkevich VB, Kudrin VS, Klodt PM, et al. Effects of Selank on monoamine neurotransmitters in the brain of BALB/c and C57BL/6 mice. Bull Exp Biol Med. 2008;145(1):68–71.
- Uchakina ON, Uchakin PN, Miasoedov NF, et al. Immunomodulatory effects of selank in patients with anxiety-asthenic disorders. Zhurnal Nevrologii i Psikhiatrii. 2008;108(5):71–75.
- Kozlovskii II, Andreeva LA, Kozlovskaya MM. The role of the endogenous opioid system in the anxiolytic action of Selank. Bull Exp Biol Med. 2012;153(5):728–730.
- Kolik LG, Nadorova AV, Kozlovskaya MM. Efficacy of Peptide Anxiolytic Selank during Modeling of Withdrawal Syndrome in Rats with Stable Alcoholic Motivation. Bull Exp Biol Med. 2014;157(1):61–65.
- Konstantinopolsky MA, Kolik LG, Chernyakova IV. Selank, a Peptide Analog of Tuftsin, Attenuates Aversive Signs of Morphine Withdrawal in Rats. Bull Exp Biol Med. 2022;173(6):730–733.
- Mukhina AY, et al. Effects of Selank on intestinal microbiota and stress-induced changes. Russian Journal of Physiology. 2019/2020.
- Kasian A, Kolomin T, Andreeva L, et al. Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats. Behavioural Neurology. 2017;2017:5091027.
- Kolik LG, Nadorova AV, Antipova TA, Durnev AD. Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content. Bull Exp Biol Med. 2019;167(5):641–644.
- Medvedev VE, Tereshchenko ON, Israelian AI, et al. A comparison of the anxiolytic effect and tolerability of selank and phenazepam. Zhurnal Nevrologii i Psikhiatrii. 2014;114(7):17–22.
- Semenova TP, Kozlovskii II, Zakharova NM, Kozlovskaya MM. Experimental optimization of learning and memory processes by selank. Eksperimental'naia i Klinicheskaia Farmakologiia. 2010;73(8):2–5.
- Filatova E, Kasian A, Kolomin T, et al. GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells. Frontiers in Pharmacology. 2017;8:89.
- Kolomin TA, Shadrina M, Andreeva LA, et al. Expression of inflammation-related genes in mouse spleen under tuftsin analog Selank. Regulatory Peptides. 2011;170(1-3):18–23.
- Andreeva LA, Nagaev IY, Mezentseva MV, et al. Antiviral properties of structural fragments of the peptide Selank. Doklady Biological Sciences. 2010;431:79–82.
Related Research Questions
Want the complete research review?
View Full Selank Research Page→FOR RESEARCH USE ONLY
This content is provided for educational and informational purposes only. Products are furnished for in-vitro studies only and are not medicines, drugs, or supplements. Not approved by the FDA to prevent, treat, or cure any condition.