Mast cells, antidepressants and chronic fatigue syndrome

肥大细胞、抗抑郁药和慢性疲劳综合症

• 批准号: 7296142
• 负责人: THEOHARIS C. THEOHARIDES
• 金额: $ 14.88万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7296142
• 关键词: Adrenal Glands; Affect; Amitriptyline; Animal Model; Antidepressive Agents; Appendix; Blood - brain barrier anatomy; Brain; Bupropion; CD34 gene; Calcium ion; Cell Line; Cell secretion; Cells; Chronic Fatigue Syndrome; Class; Clinical Trials; Coculture Techniques; Connective Tissue; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Disease; Dose; Endocrine; Fatigue; Fibromyalgia; Fluoxetine; Functional disorder; Future; Growth Factor; Histamine; Hormone Receptor; Hormones; Human; Hypothalamic structure; IL8 gene; Imipramine; Immune Sera; Immunologics; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-13; Interleukin-4; Interleukin-6; Interstitial Cystitis; Irritable Bowel Syndrome; Lead; Malaise; Mediating; Mental Depression; Migraine; Mus; Nerve; Nerve Endings; Nerve Growth Factors; Neuroglia; Neuroimmunomodulation; Neurons; Neuropeptides; Neurotensin; Norepinephrine; PC12 Cells; Pathogenesis; Permeability; Pharmaceutical Preparations; Pheochromocytoma; Pituitary Gland; Principal Investigator; Process; Rattus; Receptor Activation; Rodent; Serotonin; Serotonin Uptake Inhibitors; Sertraline; Sleep; Stem cells; Stress; Substance P; Substance P Receptor; TNF gene; Temporomandibular Joint Disorders; Time; Tricyclic Antidepressive Agents; Tryptase; Umbilical Cord Blood; Umbilical cord structure; Vascular Endothelial Growth Factors; Week; Wharton' s jelly; Xenograft procedure; acute stress; antalarmin; blastocyst; cytokine; day; disability; drug testing; embryonic stem cell; human stem cells; hypothalamic-pituitary-adrenal axis; in vitro Model; in vivo; in vivo Model; lysophosphatidylserine; mast cell; neuropsychiatry; progenitor; programs; relating to nervous system; response; reuptake; urocortin; urocortin II; urocortin III

DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is characterized by fatigue, malaise, sleep and autonomic disturbances; it is considered a neuroimmune disorder with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, precipitated by stress and associated with high disability. CFS often occurs with comorbid diseases such as fibromyalgia, irritable bowel syndrome (IBS), interstitial cystitis (IC) and migraines, all of which also worsen by stress. There are no reliable animal models for CFS. Mast cells have emerged as a major regulator of neuroimmune endocrine processes affected by stress and have been implicated in all comorbid diseases associated with CFS. We have shown that: (a) mast cells have functional associations with nerve endings; (b) acute stress activates mast cells, an action blocked by pretreatment with corticotropin-releasing hormone (CRH) neutralizing antiserum, (c) stress increases blood-brain-barrier (BBB) permeability, which is inhibited by the CRH-receptor-1 (CRH-R1) antagonist Antalarmin and does not develop in mast cell deficient W/W mice, (d) human mast cells express CRH receptors, activation of which leads to selective release of vascular endothelial growth factor (VEGF), (e) some of the stimulatory effects of CRH on mast cells are mediated by neurotensin (NT), which has been shown to regulate the HPA axis. Tricyclic antidepressants are helpful in CFS and in the other comorbid diseases, but this mechanism of action is unknown. Our preliminary results show that the tricyclic antidepressant amitriptyline can inhibit rat mast cell secretion and intracellular calcium ion levels. Hypothesis: CRH, or the structurally related urocortin (Ucn), secreted by stress activates diencephalic mast cells, either alone or together with other neuropeptides such as NT leading to release of molecules that contribute to the central pathogenesis of CFS, and secretion of which can be inhibited by tricyclic antidepressants. We will investigate: Aim 1. The dose-response (0.1-100 uM) and time-course (0.5,1,6, 24 h) effects of three different classes of antidepressants, (a) the tricyclic (amitriptyline, imipramine), (b) the selective serotonin uptake inhibitors (fluoxetine, sertraline) and (c) bupropion on secretion of histamine, IL-1, IL-6, IL-8, IL-13, TNF, tryptase and VEGF from normal human umbilical cord-derived cultured mast cells (hCBMCs) derived from CD34+ progenitors triggered by IL-1, CRH or Ucn (100 nM). Aim 2. The effect of those antidepressants shown to be effective in Aim 1 for their ability to inhibit "brain mast cells" developed by culturing human umbilical cord matrix stem cells (hCMSCs) that are CD34- in the presence of 10 nM IL-4 and nerve growth factor (NGF), stimulated as in Aim 1 +/- NT (0.1-100 mM). Results from these studies will further our understanding of molecules released in response to stress hormones and which antidepressants may be useful in inhibiting these effects. Future studies will build on these findings to develop in vitro and in vivo models of CFS and lead to clinical trials with select antidepressants or other molecules that inhibit brain mast cells.

描述（由申请人提供）：慢性疲劳综合征（CFS）以疲劳、不适、睡眠和自主神经障碍为特征；它被认为是一种下丘脑-垂体-肾上腺（HPA）轴失调的神经免疫疾病，由压力引起，并与高度残疾相关。慢性疲劳综合症通常与纤维肌痛、肠易激综合征（IBS）、间质性膀胱炎（IC）和偏头痛等共病一起发生，所有这些疾病也会因压力而恶化。目前尚无可靠的慢性疲劳综合症动物模型。肥大细胞已成为受应激影响的神经免疫内分泌过程的主要调节因子，并与CFS相关的所有合并症有关。我们已经证明：(a)肥大细胞与神经末梢具有功能关联；(b)急性应激激活肥大细胞，这一作用被促肾上腺皮质激素释放激素（CRH）中和抗血清预处理阻断；(c)应激增加血脑屏障（BBB）的通透性，这一作用被CRH受体-1 （CRH- r1）拮抗剂安塔拉明抑制，在肥大细胞缺陷的W/W小鼠中不发生；(d)人类肥大细胞表达CRH受体，其激活导致血管内皮生长因子（VEGF）的选择性释放。(e) CRH对肥大细胞的一些刺激作用是由神经紧张素（NT）介导的，神经紧张素已被证明可以调节HPA轴。三环抗抑郁药对慢性疲劳综合症和其他合并症有帮助，但其作用机制尚不清楚。我们的初步结果表明，三环抗抑郁药阿米替林可以抑制大鼠肥大细胞分泌和细胞内钙离子水平。假设：应激分泌的CRH或与结构相关的尿皮质素（Ucn）激活间脑肥大细胞，单独或与其他神经肽（如NT）一起，导致导致CFS核心发病机制的分子释放，其分泌可被三环抗抑郁药抑制。我们将调查：目标1。三种不同类型的抗抑郁药(a)三环（阿米替林、丙咪嗪），(b)选择性5 -羟色胺摄取抑制剂（氟西汀、舍曲林）和(c)安非他酮对IL-1、CRH或Ucn （100 nM）触发的CD34+祖细胞衍生的正常人脐带培养肥大细胞（hCBMCs）分泌组胺、IL-1、IL-6、IL-8、IL-13、TNF、胰蛋白酶和VEGF的剂量反应（0.1-100 μ m）和时间过程（0.5、1、6、24 h）的影响。目标2。这些抗抑郁药的效果在Aim 1中被证明是有效的，因为它们能够抑制通过培养CD34-的人脐带基质干细胞（hCMSCs）产生的“脑肥大细胞”，在10 nM IL-4和神经生长因子（NGF）的存在下，在Aim 1 +/- NT （0.1-100 mM）中受到刺激。这些研究的结果将进一步加深我们对应激激素释放的分子的理解，以及哪种抗抑郁药可能有助于抑制这些作用。未来的研究将以这些发现为基础，开发体外和体内CFS模型，并选择抗抑郁药或其他抑制脑肥大细胞的分子进行临床试验。