Interactions Between Depression, Neuroinflammation and Glycogen Synthase Kinase-3

抑郁症、神经炎症和糖原合酶激酶 3 之间的相互作用

• 批准号: 8465908
• 负责人: Eleonore Beurel
• 金额: $ 19.1万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465908
• 关键词: Address; Adjuvant; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Astrocytes; Autopsy; Behavior; Behavioral; Biochemical; Biological Models; Brain; Chronic; Cognition; Depressed mood; Disease; Emotions; Epigenetic Process; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Glycogen Synthase Kinase 3; Goals; Heterogeneity; High Prevalence; Host Defense; Human; Immune; Immune system; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-6; Lead; Learned Helplessness; Life Experience; Link; Lithium; Major Depressive Disorder; Malignant Neoplasms; Mediating; Mental Depression; Mentors; Microglia; Modeling; Mood Disorders; Mood stabilizers; Moods; Mus; Natural Immunity; Nerve Degeneration; Nervous system structure; Neuroglia; Neurons; Outcome; Patients; Population; Predisposition; Process; Production; Psychological Stress; Reaction; Research; Resistance; Rodent; Role; Sampling; Serum; Signal Transduction; Stimulus; Stress; System; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Training; United States; adaptive immunity; base; behavioral impairment; cytokine; depressive symptoms; design; immune activation; improved; inflammatory marker; inhibitor/antagonist; mood regulation; neuroinflammation; neurotrophic factor; response; response to injury; therapy development

ABSTRACT Accumulating evidence shows inflammation strongly influences the development and treatment of depression, a debilitating disease with a lifetime incidence of ~20%. Markers of Inflammation often are increased in the serum of depressed patients, interferon administration can induce depression, "psychological" stresses that can induce depression increase inflammatory cytokines in humans and rodents, administration of inflammatory cytokines induces depression-like behaviors in rodents, in humans increased cytokines associated with a mild stimulation of the primary host defense system has negative effects on emotions, antidepressants have anti-inflammatory effects, and immune activation in patients with major depression is associated with resistance to antidepressant treatment. Therefore, in order to understand and design improved therapeutics for depression, it is important to identify mechanisms regulating neuroinflammation, inflammatory molecule accumulation in the CNS. Glycogen synthase kinase-3 (GSK3) recently was found to be a powerful regulator of cytokine production in the periphery. We extended this to the CNS, e.g., showing that GSK3 inhibitors reduce by >90% the production of the proinflammatory cytokine interleukin-6 in astrocytes and microglia. We also found that GSK3 inhibitors promote tolerance to inflammation, down-regulating inflammatory responses to repeated inflammatory stimuli, which may be particularly important in controlling chronic inflammation that is likely associated with mood disorders. GSK3 also has profound influences in mood disorders, it is inhibited by mood stabilizers and antidepressants, pharmacological or genetic reduction of GSK3 activity reduces depression-like behaviors in rodents, and evidence in postmortem brain samples and serum from humans indicate GSK3 is abnormally active in mood disorders. We recently found GSK3 is activated in mouse brain by the learned helplessness model of depression. Taken together, these findings suggest that the pro-inflammatory action of GSK3 may contribute to its promotion of mood disorders, and that the therapeutic actions of mood stabilizers and antidepressants that inhibit GSK3 may involve anti-inflammatory effects. Thus, studies of the inflammation system provide a model system to study how GSK3 regulates key processes that are likely involved in mood disorders: epigenetics, tolerance, and behavior. These aims provide independent but associated goals that will identify new mechanisms by which dysregulated GSK3 can contribute to mood disorders and identify how therapeutic interventions ameliorate these outcomes. Specific Aim 1 will test the hypothesis that GSK3 regulates innate and adaptive immune system in the brain during depressive-like behavior. Specific Aim 2 will test the hypothesis that GSK3 regulates epigenetics, using changes induced by inflammatory stimuli as a model. Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress.

摘要 越来越多的证据表明炎症强烈影响着疾病的发展和治疗 抑郁症是一种使人衰弱的疾病，终生发病率约为20%。炎症标志物通常 在抑郁症患者的血清中增加，干扰素给药可诱导抑郁症， “心理”压力会导致抑郁症，增加人类的炎症细胞因子， 在啮齿类动物中，给予炎性细胞因子诱导抑郁样行为， 人类增加的细胞因子与初级宿主防御系统的轻度刺激有关 对情绪有负面影响，抗抑郁药有抗炎作用，免疫 重度抑郁症患者的激活与抗抑郁治疗的抵抗有关。 因此，为了理解和设计改进的抑郁症治疗方法，重要的是 确定调节神经炎症、CNS中炎症分子积聚的机制。 糖原合成酶激酶3（Glycogen synthase kinase-3，GSK 3）是近年来发现的一种强有力的细胞因子调节因子， 外围生产。我们将其扩展到CNS，例如，显示GSK 3抑制剂减少了 星形胶质细胞和小胶质细胞中促炎细胞因子白细胞介素-6的产生减少>90%。我们 还发现GSK 3抑制剂促进对炎症的耐受性，下调炎症反应， 对反复炎症刺激的反应，这可能在控制慢性炎症中特别重要。 可能与情绪障碍有关的炎症。GSK 3也对人类的健康产生了深远的影响。 情绪障碍，它是抑制情绪稳定剂和抗抑郁药，药理学或遗传 GSK 3活性的降低可减少啮齿动物的抑郁样行为以及尸检证据 来自人类的脑样品和血清表明GSK 3在情绪障碍中异常活跃。我们 最近发现GSK 3在小鼠大脑中被抑郁症的习得性无助模型激活。 综上所述，这些发现表明GSK 3的促炎作用可能有助于其在炎症反应中的作用。 情绪稳定剂和抗抑郁药的治疗作用 抑制GSK 3可能涉及抗炎作用。 因此，炎症系统的研究提供了一个模型系统，以研究如何GSK 3 调节可能涉及情绪障碍的关键过程：表观遗传学，耐受性， 行为这些目标提供了独立但相关的目标，这些目标将通过以下方式确定新的机制： 哪些GSK 3失调会导致情绪障碍，并确定治疗干预如何 改善这些结果。具体目标1将检验GSK 3调节先天性和 适应性免疫系统在大脑中的抑郁样行为。具体目标2将测试 假设GSK 3调节表观遗传学，利用炎症刺激诱导的变化作为一种调节因子， 模型具体目标3将检验GSK 3促进抑郁样行为的假设。 对炎症和环境压力的反应。