Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression.
Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression.
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DOI：
10.1371/journal.pone.0163992
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Fukunaga K
中科院分区：
文献类型：
--
作者：
Shinoda Y;Tagashira H;Bhuiyan MS;Hasegawa H;Kanai H;Zhang C;Han F;Fukunaga K
心血管疾病是人类抑郁症的危险因素。我们最近提出，在小鼠中，刺激σ1受体（σ 1 R）可挽救由横向主动脉缩窄（TAC）引起的心脏肥大和心力衰竭。重要的是，据报道，σ 1 R刺激改善了啮齿动物的抑郁样行为。因此，我们假设脑中σ 1 R活性受损触发心血管疾病动物的抑郁样行为。事实上，我们发现TAC诱导的心脏肥大和心力衰竭与术后6周脑中σ 1 R表达下调伴随的抑郁样行为有关。海马CA 1区和齿状回星形胶质细胞σ 1 R水平显著降低。口服特异性σ 1 R激动剂SA 4503（0.3-1.0mg/kg）可显著改善TAC诱导的抑郁样行为，并可挽救海马CA 1区和齿状回的σ 1 R表达。血浆皮质酮水平在TAC后6周显著升高，并且用皮质酮慢性治疗小鼠3周引起抑郁样行为，伴随海马星形胶质细胞σ 1 R表达减少。此外，糖皮质激素受体拮抗剂米非司酮可拮抗TAC小鼠的抑郁样行为，并改善其海马σ 1 R表达的下降。我们得出结论，皮质酮水平升高触发海马σ 1 R下调，SA 4503刺激σ 1 R是一种有吸引力的治疗方法，不仅可以改善心功能障碍，还可以改善与心力衰竭相关的抑郁样行为。
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.
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