GSB-106 Dipeptide Mimetic of Brain-Derived Neurotrophic Factor Prevents Anhedonia Development under Acute Social Defeat
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Pharmaceutical Chemistry Journal, Vol. 54, No. 5, August, 2020 (Russian Original Vol. 54, No. 5, May, 2020)
MOLECULAR-BIOLOGICAL PROBLEMS OF DRUG DESIGN AND MECHANISM OF DRUG ACTION GSB-106 DIPEPTIDE MIMETIC OF BRAIN-DERIVED NEUROTROPHIC FACTOR PREVENTS ANHEDONIA DEVELOPMENT UNDER ACUTE SOCIAL DEFEAT STRESS CONDITIONS IN MICE A. V. Tallerova,1 A. G. Mezhlumyan,1 P. Yu. Povarnina,1 T. A. Antipova,1 I. O. Logvinov,1 T. A. Gudasheva,1,* and S. B. Seredenin1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 5, pp. 3 – 6, May, 2020.
Original article submitted September 9, 2019. The influence of the dimeric dipeptide mimetic of brain-derived neurotrophic factor (BDNF) bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106, dosage form) during three-day peroral administration at a dose of 0.1 mg/kg on the 1% sucrose solution preference test and the content of postsynaptic density protein (PSD-95) in the prefrontal cortex and hippocampus of C57Bl/6 mice was studied in an acute three-day social defeat stress model. The preference for sucrose solution decreased and the PSD-95 content in the prefrontal cortex was halved statistically significantly in stressed mice as compared to control animals. The hippocampal PSD-95 content in stressed animals did not change. Anhedonia was completely prevented after each stress session according to the sucrose preference test with peroral administration of GSB-106 at a dose of 0.1 mg/kg once per day for three days. GSB-106 did not reduce the prefrontal PSD-95 content of stressed animals during the experiment. Keywords: BDNF, dipeptide mimetic GSB-106, anhedonia, postsynaptic density protein PSD-95, acute social defeat stress.
GSB-106, the substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, is a promising antidepressant mimetic of the fourth loop of brain-derived neurotrophic factor (BDNF) that was developed at Zakusov State Institute of Pharmacology [1]. Previously, GSB-106 was shown to activate TrkB receptors and MAPK/ERK and P13K/AKT signaling pathways [2, 3]. GSB-106 demonstrated the ability to stimulate hippocampal synapto- and neurogenesis in mouse experiments [3, 4]. GSB-106 exhibited antidepressant activity in several tests on rodents after i.p. (0.1 – 1.0 mg/kg) and peroral (0.5 – 1 *
5.0 mg/kg) administration [5, 6]. GSB-106 at doses of 0.05 – 1.0 mg/kg in a tablet dosage form (DF) exhibited antidepressant activity [7, 8]. Acute stress is known to diminish the length of apical dendrites and to decrease the synthesis of synaptic proteins and the number of dendritic spines in the frontal cortex [9 – 12]. Similar changes were considered a predisposing factor of depression, which agreed with the neuroplastic theory of the development of psychic diseases [9]. Experimental studies also found that a decrease of the membrane protein/receptor density in the frontal cortex of mice in an acute social defeat stress model was associated with the development of depression symptoms, in particular, anhedonia [12]. Therefore, it co
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