NADPH oxidase mediates depressive behavior induced by chronic stress in mice.
Stress is a potent risk factor for depression, yet the underlying mechanism is not clearly understood. In the present study, we explored the mechanism of development and maintenance of depression in a stress-induced animal model. Mice restrained for 2 h daily for 14 d showed distinct depressive behavior, and the altered behavior persisted for >3 months in the absence of intervention. Acute restraint induced a surge of oxidative stress in the brain, and stress-induced oxidative stress progressively increased with repetition of stress. In vitro, the stress hormone glucocorticoid generated superoxide via upregulation of NADPH oxidase. Consistently, repeated restraints increased the expression of the key subunits of NADPH oxidase, p47phox and p67phox, in the brain. Moreover, stressed brains markedly upregulated the expression of p47phox to weak restress evoked in the poststress period, and this molecular response was reminiscent of amplified ROS surge to restress. Pharmacological inhibition of NADPH oxidase by the NADPH oxidase inhibitor apocynin during the stress or poststress period completely blocked depressive behavior. Consistently, heterozygous p47phox knock-out mice (p47phox(+/-)) or molecular inhibition of p47phox with Lenti shRNA-p47phox in the hippocampus suppressed depressive behavior. These results suggest that repeated stress promotes depressive behavior through the upregulation of NADPH oxidase and the resultant metabolic oxidative stress, and that the inhibition of NADPH oxidase provides beneficial antidepression effects.
Department of Brain and Cognitive Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
Ji-Seon
JS
Seo
Jin-Young
JY
Park
Juli
J
Choi
Tae-Kyung
TK
Kim
Joo-Hyun
JH
Shin
Ja-Kyeong
JK
Lee
Pyung-Lim
PL
Han
D000098:Acetophenones / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage; D000975:Antioxidants / Q000008:administration & dosage; D001205:Ascorbic Acid / Q000008:administration & dosage; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D003866:Depressive Disorder / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007099:Imipramine / Q000008:administration & dosage; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012149:Restraint, Physical / Q000009:adverse effects*; D012919:Social Behavior; D013481:Superoxides / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D013997:Time Factors
D000098:Acetophenones; D000929:Antidepressive Agents, Tricyclic; D000975:Antioxidants; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D049452:Green Fluorescent Proteins; C056165:acetovanillone; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D007099:Imipramine; D001205:Ascorbic Acid; D003345:Corticosterone