Antidepressant effects of TBE-31 and MCE-1, the novel Nrf2 activators, in an inflammation model of depression.
The Nuclear factor (erythroid 2-derived)-like 2 (Nrf2) plays a key role in inflammation which is implicated in the pathophysiology of depression. The Nrf2 activators have antidepressant effects in animal models of depression. The present study was undertaken to examine whether TBE-31 [(±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile] and MCE-1 [(±)-3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile], the novel Nrf2 activators, could show antidepressant effects in inflammation model of depression. We found that TBE-31 and MCE-1 significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The Nrf2 siRNA, but not negative control of siRNA, significantly blocked the potentiating effects of TBE-31 and MCE-1 on neurite outgrowth in PC12 cells. Furthermore, oral administration of TBE-31 or MCE-1 significantly attenuated an increase in serum levels of tumor necrosis factor-α (TNF-α) after administration of lipopolysaccharide (LPS: 0.5mg/kg). In the tail-suspension test and forced swimming test, oral administration of TBE-31 or MCE-1 significantly attenuated an increase in the immobility time after LPS (0.5mg/kg) administration. These findings suggest that the novel Nrf2 activators such as TBE-31 and MCE-1 might be potential therapeutic drugs for inflammation-related depression.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Wei
W
Yao
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Ji-Chun
JC
Zhang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Tamaki
T
Ishima
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Qian
Q
Ren
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Chun
C
Yang
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Chao
C
Dong
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Min
M
Ma
Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
Akira
A
Saito
Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States.
Tadashi
T
Honda
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address: hashimoto@faculty.chiba-u.jp.
Kenji
K
Hashimoto
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D000071446:Neuronal Outgrowth / Q000187:drug effects; D016716:PC12 Cells; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C000616096:3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile; D000928:Antidepressive Agents; D003512:Cyclohexanones; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D010616:Phenanthrenes; C531972:TBE 31; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor
Antidepressant; Inflammation; MCE-1; Neurite outgrowth; Nrf2; TBE-31