Z-Guggulsterone Produces Antidepressant-Like Effects in Mice through Activation of the BDNF Signaling Pathway

Abstract

Background:Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression.Methods:The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone.Results:Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone.Conclusions:Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis.

The ketone body metabolite β‐hydroxybutyrate induces an antidepression‐associated ramification of microglia via HDACs inhibition‐triggered Akt‐small RhoGTPase activation

“…The sucrose preference experiment was performed at day 37. The experimental mice were given the choice to drink from two bottles in individual cages, one with 1% sucrose solution and the other with water (Liu et al, ). All were acclimatized for 2 days to two‐bottle choice conditions, and the position of two bottles was changed every 6 hr to prevent possible effects of side preference in drinking behavior.…”

Lipopolysaccharide-Induced Depression-Like Behaviors Is Ameliorated by Sodium Butyrate via Inhibiting Neuroinflammation and Oxido-Nitrosative Stress

“…In this experiment, the mice with or without LPS and/or SB treatment were given a choice to drink from 2 bottles in individual cages (one with 1% sucrose solution and the other with water) [32], and these mice were acclimatized for 2 days to this choice condition, during which the position of the 2 bottles was changed every 6 h. Once the acclimation is finished, the mice were deprived of water and food for 24 h, and on the testing day, each mouse was exposed to pre-weighed bottles for 3 h with their positions interchanged. The sucrose preference was calculated as a percentage of the consumed sucrose solution relative to the total amount of liquid intake.…”

“…This experiment was performed according to one of our previous studies [32]. The spontaneous activity of the mice in the OFT was evaluated in the open-field paradigm over a 5-min period.…”

Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors and Prevents Dendritic Spine Loss in Mice Hippocampi

“…Our previous studies also revealed that PDE4 modulated the development of negative emotional reactions associated with ethanol abstinence, including depression (Gong et al, 2017). Activated CREB promotes the transcription of brain-derived neurotrophic factor (BDNF), which is a potent trophic factor that maintains the morphology of neurons and mediates synaptic plasticity (ZZ Wang et al, 2013; Liu et al, 2017). The concentration of BDNF in the brain is reduced in patients with major depressive disorder, and antidepressant treatment may improve or normalize cerebral concentrations of BDNF (Sheldrick et al, 2017).…”