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



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.



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.



Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis.
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Feng-Guo
FG
Liu
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Wen-Feng
WF
Hu
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Ji-Li
JL
Wang
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Peng
P
Wang
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Yu
Y
Gong
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Li-Juan
LJ
Tong
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Bo
B
Jiang
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Wei
W
Zhang
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Yi-Bin
YB
Qin
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Zhuo
Z
Chen
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Rong-Rong
RR
Yang
Department of Neurology, Danyang People's Hospital, Danyang, Jiangsu, China (Mr Liu); Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Drs Qin and Yang); Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Tong, Jiang, and Zhang); Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong, Jiangsu, China (Drs Huang, Hu, J.-L. Wang, P. Wang, Gong, Tong, Jiang, and Zhang); Invasive Technology Department, Nantong First People's Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (Dr Chen).
Chao
C
Huang
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D011282:Pregnenediones / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D011282:Pregnenediones; D005473:Fluoxetine; C023617:pregna-4,17-diene-3,16-dione; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
BDNF; CREB; CUS; Z-guggulsterone; major depression