Rapid Antidepressant Effect of Hydrogen Sulfide: Evidence for Activation of mTORC1-TrkB-AMPA Receptor Pathways.
We asked whether hydrogen sulfide (H2S), as the third gaseous mediator, provided fast antidepressant effect on major depressive disorders and underlying mechanisms.



The decreased level of H2S was detected in the hippocampus of chronic unpredictable mild stress (CUMS)-treated rats. Acute administration of H2S either by H2S inhalation or by the donor NaHS produced a rapid antidepressant-like behavioral effect. Further investigation demonstrated that this effect of H2S was mediated by reversing the CUMS-induced decrease in dendritic spine density and required the activation of mammalian target of rapamycin (mTOR)C1 and neurotrophic TrkB receptors, which proceeded to increase synaptic protein expression, including postsynaptic density protein 95, synaptophysin, and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor GluR1/2 subunit.



This study provides the first direct evidence for detecting the decreased H2S in hippocampus of CUMS rats and the biological significance of H2S in treating major depression.



Our data demonstrate that H2S activates mTORC1 signaling cascades and thereby produces fast-onset antidepressant effect. The study provides a profound insight into H2S or its donors as potent preventive and therapeutic agents for intervention of depression. Antioxid. Redox Signal. 27, 472-488.
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Xiao-Yi
XY
Hou
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .|2 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (Huazhong University of Science and Technology) , Wuhan, China .|3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology , Wuhan, China .|4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .
Zhuang-Li
ZL
Hu
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Deng-Zheng
DZ
Zhang
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Wei
W
Lu
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Jun
J
Zhou
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .|2 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (Huazhong University of Science and Technology) , Wuhan, China .|3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology , Wuhan, China .|4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .
Peng-Fei
PF
Wu
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Xin-Lei
XL
Guan
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Qian-Qian
QQ
Han
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .
Si-Long
SL
Deng
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .|4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .|5 Collaborative Innovation Center for Brain Science , Wuhan, China .
Hai
H
Zhang
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .|2 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (Huazhong University of Science and Technology) , Wuhan, China .|3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology , Wuhan, China .|4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .|5 Collaborative Innovation Center for Brain Science , Wuhan, China .
Jian-Guo
JG
Chen
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China .|2 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (Huazhong University of Science and Technology) , Wuhan, China .|3 Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology , Wuhan, China .|4 Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China , Wuhan, China .|5 Collaborative Innovation Center for Brain Science , Wuhan, China .
Fang
F
Wang
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000928:Antidepressive Agents; D006862:Hydrogen Sulfide; D000076222:Mechanistic Target of Rapamycin Complex 1; D020813:Receptor, trkB; D018091:Receptors, AMPA; C000621230:Ntrk2 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2
TrkB receptors; antidepressant; chronic unpredictable mild stress; hydrogen sulfide; mTORC1; major depressive disorders