HBK-15 protects mice from stress-induced behavioral disturbances and changes in corticosterone, BDNF, and NGF levels

Abstract

Unlike majority of current antidepressants, HBK-15-a 5-HT_1A and 5-HT₇ receptor antagonist - showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (t_max=5min), a short half-life (t_0.5=74min), large volume of distribution (V_ss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT_1A and 5-HT₇ receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction.

Keywords: 5-HT(1A) receptor antagonist; 5-HT(7) receptor antagonist; CD-1 mice; LC/MS/MS; Pharmacokinetics; Unpredictable chronic mild stress.