|Alternative Title||The effect of blockade of glucocorticoid receptor on lipopolysaccharide-induced depressive-like behavior and proinflammatory cytokines in rats|
抑郁症是危害人类健康的主要心理疾病之一，其病因机制至今未得到完全阐明。“抑郁症的细胞因子假说”强调抑郁症是一种心理神经免疫紊乱性障碍，已成为近二十多年来的研究热点。但该假说不能解释细胞因子引起抑郁症的个体易感性差异。本研究提出糖皮质激素受体（glucocorticoid receptor，GR）功能状态可作为个体易感性的决定因素而参与细胞因子所致抑郁症形成的可能性。 为探讨GR在炎性细胞因子所致抑郁样行为中的作用，明确GR功能变化是否参与炎性细胞因子所致抑郁症的病理生理机制，本研究使用GR阻断剂RU486（RU），分别以RU单次、反复或持续外周注射几种不同阻断方式，考察阻断GR功能对急性或慢性外周注射脂多糖（lipopolysaccharide，LPS）免疫激活所诱导的大鼠抑郁样行为和炎性细胞因子时程变化的影响。以糖精水偏爱分数、旷场活动性、悬尾静止时间作为抑郁样行为的考察指标，以肿瘤坏死因子α（tumor necrosis factor α, TNFα）、白介素-1β（interleukin-1β, IL-1β）、干扰素γ（interferonγ, IFNγ）作为炎性细胞因子的考察指标。 主要实验结果如下： 1. 急性LPS免疫激活引起显著但短暂的炎性细胞因子增多和抑郁样行为；而慢性LPS免疫激活没有引起任何显著的炎性细胞因子增多和抑郁样行为； 2. 单次RU处理对急性LPS免疫激活所致的短暂的炎性细胞因子增多和抑郁样行为没有显著影响；反复RU处理使急性LPS免疫激活所致的炎性细胞因子增多和抑郁样行为显著延长；持续RU处理和慢性LPS免疫激活引起显著而持久的炎性细胞因子增多和抑郁样行为； 3. 单次RU本身既没有引起显著的炎性细胞因子增多，也没有引起显著的抑郁样行为；反复或持续RU本身虽未引起显著的炎性细胞因子增多，但引起显著的抑郁样行为，但其行为效应的程度显著弱于反复或持续RU与LPS的共同作用。 以上结果提示，GR功能正常者不易受急性或慢性免疫激活的作用而形成持久的炎性细胞因子分泌增加及抑郁，而GR功能异常者则容易受急性或慢性免疫激活的作用而形成持久的炎性细胞因子分泌增加及抑郁。在GR功能异常的情况下，免疫激活所致抑郁样行为的形成不仅与炎性细胞因子的变化有关，而且与HPA轴功能变化有关。正常GR具有保护个体避免炎性细胞因子过度活动及相关抑郁症侵袭的重要功能，而异常GR则可能是炎性细胞因子过度活动及相关抑郁症形成的重要内在条件或参与因素。不同个体GR功能状态的差异可能决定着个体对细胞因子所致抑郁症的易感性的差异。本研究提供的证据是对抑郁症细胞因子假说的重要补充，可为细胞因子导致抑郁症的病机理论增添新的解释。
Depression is one of the most disabling mental diseases with unknown pathogenesis. Understanding the pathological mechanism of this mood disorder is the foundation for its effective treatment and rehabilitation care. The “cytokine hypothesis of depression”, which has been a research focus for two decades, emphasized that depression may be a psychoneuroimmunological disorder in nature. This hypothesis, however, failed to give a clear explanation for the differences in the susceptibility to cytokine-induced depression among individuals. The present study proposes the functional state of glucocorticoid receptor (GR) as a contributing factor to the development of cytokine-induced depression for susceptible individuals. To examine the influence of GR on the development of cytokine-related depression and to determine whether the functional changes of GR is involved in the pathophysiology of cytokine-induced depression, the present study investigated the effects of different regime of administration of RU486 (RU), a potent GR antagonist, on the depressive-like behavior and cytokine production induced by lipopolysaccharides (LPS) in rats. The behavioral measurements included saccharin preference, locomotor activity, and immobility time. The serum levels of cytokine including tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interferon γ (IFNγ) were determined by ELISA. The main results are as follows: 1. Acute administration of LPS induced significant but transient increase in proinflammatory cytokine production and depressive-like behavior; Chronic administration of LPS did not induce any significant increase in proinflammatory cytokine production and depressive-like behavior; 2. No significant effect of acute administration LPS with single RU pretreatment was found in proinflammatory cytokine production and depressive-like behavior; Repeated RU pretreatment, however, significantly prolonged the increase in proinflammatory cytokine production and depressive-like behavior induced by acute administration LPS; Continuous RU treatment in combination with chronic administration of LPS induced significantly sustained increase in proinflammatory cytokine production and depressive-like behavior; 3. Single RU treatment per se induced neither any significantly increase in proinflammatory cytokine production nor any depressive-like behavior; Without any observed increase in proinflammatory cytokine production, repeated or continuous RU treatment per se induced some extent of depressive-like behavior, although less significant in magnitude as compared to the combined action of both RU and LPS. These results suggest that individuals with normal GR function are less susceptible to acute or chronic immune activation, thereby are not easy to be involved in sustained activation of proinflammatory cytokine and development of depression, while those with GR dystunction tend to be easily affected by acute or chronic immune activation and subsequent sustained hyper-activity of proinflammatory cytokine and development of depression. In the case of GR dysfunction, the development of depression induced by immune activation is related not only to proinflammatory cytokine activities, but also to HPA axis activities. GR dysfunction may be an important internal cause or a contributing factor to the development of depression induced by cytokines. The differences in the susceptibility to cytokine-induced depression among individuals may be due to the differences of GR function among them. The present study provides evidence for completing the cytokine hypothesis of depression, and may add to the growing body of knowledge as to the mechanisms by which cytokine influences depression.
|Keyword||细胞因子 抑郁样行为 糖皮质激素受体 脂多糖 RU486|
|Place of Conferral||北京|
|王东林. 阻断糖皮质激素受体对免疫激活所致抑郁样行为和炎性细胞因子的影响[D]. 北京. 中国科学院研究生院,2010.|
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