Ī tablet dosage form of GSB-106 for oral administration was developed in the Technological Department of the Institute (application for a patent of the Russian Federation 2018107362 from 28 02 2018) to create a drug on the basis of the substance. GSB-106 was also shown to stimulate neurogenesis and synaptogenesis in mouse hippocampus. GSB-106 demonstrated antidepressant activity at intraperitoneal (i.p.) (0.1–1.0 mg/kg) and oral (0.5–5.0 mg/kg) administration in a number of rodent tests. GSB-106 was established to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways-PI3K/AKT and MAPK/ERK. Zakusov Research Institute of Pharmacology. Thus, both pathophysiological evidence and results of experimental and clinical pharmacological studies demonstrate the feasibility of using the BDNF-TrkB receptor system as a pharmacological target of search for new antidepressants.Ī mimetic of the fourth loop of BDNF, GSB-106, which is a substituted dimeric dipeptide, bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized in the V. The data proving that mTOR inhibition leads to the disappearance of ketamine antidepressant effects serve as pharmacological confirmation of this conclusion. From the theoretical point of view, the most important fact is that antidepressant effect of ketamine and other glutamatergic drugs is mediated by activation of BDNF-TrkB-Akt-mTORC1-signaling cascade which leads to enhanced synaptogenesis. To date, one of them, rapastinel, a modulator of NMDA receptors, is in a third phase of clinical trials. įollowing the discovery of antidepressant properties of ketamine, over the past decade, a lot of efforts have been made to create new antidepressants with a glutamatergic mechanism of action without ketamine-like side effects. Antidepressant activity was also experimentally established for BDNF mimetic 7,8-dihydroxyflavone, an antagonist of BDNF-specific TrkB receptors. The antidepressant effect of neurotrophin was revealed after central administration in different depression models in rodents. The antidepressant properties of BDNF were investigated based on its physiological functions. A reduced BDNF content in the prefrontal cortex and hippocampus was found in suicide victims. The clinical evidence demonstrates that BDNF levels in blood plasma decrease in depression and resolve as the result of antidepressant therapy. Therefore, the creation of antidepressants with new action mechanisms is regarded as one of the most pressing pharmacology problems.įundamental studies established that the pathogenesis of depression was associated with impaired neuroplasticity in the hippocampus and the prefrontal cortex, caused by deficit of brain-derived neurotrophic factor (BDNF). Modern antidepressants require long-term use to achieve a therapeutic effect, while their effectiveness does not exceed 60%. According to the WHO data in 2012, there were more than 350 million people suffering from depression. Depression is one of the most widespread mental disorders leading to social disadaptation.
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