title: Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression.
abstract: Cardiovascular diseases are risk factors for depression in humans. We recently proposed that σ1 receptor (σ1R) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, σ1R stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired σ1R activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of σ1R expression in brain 6 weeks after surgery. σ1R levels significantly decreased in astrocytes in both the hippocampal CA1 region and dentate gyrus. Oral administration of the specific σ1R agonist SA4503 (0.3-1.0mg/kg) significantly improved TAC-induced depression-like behaviors concomitant with rescued astrocytic σ1R expression in CA1 and the dentate gyrus. Plasma corticosterone levels significantly increased 6 weeks after TAC, and chronic treatment of mice with corticosterone for 3 weeks elicited depression-like behaviors concomitant with reduced astrocytic σ1R expression in hippocampus. Furthermore, the glucocorticoid receptor antagonist mifepristone antagonized depressive-like behaviors and ameliorated decreased hippocampal σ1R expression in TAC mice. We conclude that elevated corticosterone levels trigger hippocampal σ1R downregulation and that σ1R stimulation with SA4503 is an attractive therapy to improve not only cardiac dysfunction but depression-like behaviors associated with heart failure.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.affiliation: Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
authors.forename: Md Shenuarin
authors.initials: MS
authors.lastname: Bhuiyan
authors.affiliation: Department of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Electrical Engineering, Graduate School of Biomedical Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanai
authors.affiliation: Department of Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 31005, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 31005, P. R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D006332:Cardiomegaly / Q000150:complications / Q000000981:diagnostic imaging; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004452:Echocardiography; D006333:Heart Failure / Q000150:complications / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015735:Mifepristone / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D010879:Piperazines; D017480:Receptors, sigma; D015735:Mifepristone; D000255:Adenosine Triphosphate; C101789:SA 4503; D003345:Corticosterone