Mechanisms of sustained anti-neuroinflammatory actions of (2R, 6R)-hydroxynorketamine (HNK)

(2R,6R)-羟基去甲氯胺酮 (HNK) 持续抗神经炎症作用的机制

• 批准号: 9891545
• 负责人: Sarah Michelle Clark
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891545
• 关键词: Advanced Development; Affect; Affective; Allergic; Anesthetics; Anhedonia; Anti-Inflammatory Agents; Antidepressive Agents; Anxiety; Asthma; Atherosclerosis; Autoimmune Process; Behavior; Brain; Chronic; Chronic Fatigue Syndrome; Cognition; Complex; Complex Regional Pain Syndromes; Development; Disease; Disease remission; Dose; Electroencephalography; Emotional; Emotional Disturbance; Etiology; Experimental Models; Exploratory/Developmental Grant; Fibromyalgia; Genetic Transcription; Human; Immune; Impaired cognition; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Ketamine; Label; Lead; Lipopolysaccharides; Mediating; Mediator of activation protein; Medical; Mental Depression; Metabolism; Modeling; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Neuraxis; Neuronal Plasticity; Neurosecretory Systems; Operative Surgical Procedures; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Population; Process; Production; Property; Psoriasis; Psyche structure; Reaction; Receptor Inhibition; Recurrence; Reporting; Research; Rheumatoid Arthritis; Rodent Model; Role; Source; Superantigens; Telemetry; Temperature; Testing; Treatment Efficacy; Ulcerative Colitis; Work; antidepressant effect; base; chronic inflammatory disease; cytokine; emotion regulation; experimental study; follow-up; high risk; mouse model; neurobehavioral; neuroimmunology; neuroinflammation; neurotransmission; neutralizing antibody; pre-clinical; prevent; sedative; side effect; stem; stressor

Research in the field of neuroimmunology, including work from our group, has shown that peripheral and systemic inflammation is transduced into the central nervous system (CNS) by several mechanisms resulting in neuroinflammatory processes characterized by increased expression of cytokines and other inflammatory mediators. These mechanisms have been shown to affect neuroendocrine function, monoaminergic neurotransmission and neuronal plasticity negatively impacting brain function and behavior. These processes have been associated with the high incidence of emotional and cognitive impairments in people suffering from chronic inflammatory diseases such as autoimmune, allergic and systemic inflammatory diseases. Despite the broad use of current anti-inflammatory drugs to treat these conditions, they are ineffective in ameliorating the neurobehavioral component, which has been related to the persistence of neuroinflammation once it is triggered from the periphery. Therefore, there is the need to find new treatment options targeting these neuroinflammatory processes. It has been long known that the anesthetic drug ketamine has anti-inflammatory properties in surgical settings. Using rodent models, it has been shown that KET reduces inflammatory molecules in the brain triggered by immune and psychogenic stressors, offering hope for the use of KET as an anti-neuroinflammatory drug in humans. However, the dissociative, addictive, and sedative effects are limitations for the development of KET based therapies. Our preliminary studies reveal that a metabolite of KET, (2R, 6R)-hydroxynorketamine (HNK), which lacks the sedative and addictive effects of KET, possesses powerful anti-neuroinflammatory properties in the mouse model of peripheral administration of bacterial lipopolysaccharides (LPS). Notably, our preliminary studies also revealed that HNK administered alone induces sustained transcription in the brain of the cytokine IFN-g, raising the possibility that HNK mediates these effects through the production of this cytokine. The present application will comprehensively assess the anti-neuroinflammatory properties of HNK and test the role of IFN-g in mediating HNK effects in two models of peripherally-induced neuroinflammation using LPS or bacterial superantingens (SEA). In specific aim #1 we will characterize the dose, timing and effects of HNK on CNS inflammatory processes, as well as identify the cellular source of IFN-g production in the CNS induced by HNK. We will also evaluate whether metabolism of KET to HNK is required for sustained anti-neuroinflammatory effects of KET. In specific aim #2 we will utilize mice lacking IFN-g, as well as pharmacological blockade of IFN-g using neutralizing antibodies, to test the role of this cytokine in the anti-neuroinflammatory effects of HNK. We will also test if this cytokine is required for HNK antidepressant actions in the LPS model. This aim will also employ telemetry to monitor activity, temperature and EEG power bands. If successful, these exploratory/developmental studies will provide the basis for a follow-up R01 application to determine HNK-induced IFN-g anti-neuroinflammatory mechanisms.

神经免疫学领域的研究，包括我们小组的工作，表明外周和 全身性炎症通过几种机制转导到中枢神经系统（CNS）， 以细胞因子和其他炎性因子表达增加为特征的神经炎性过程 调解员这些机制已被证明影响神经内分泌功能，单胺能 神经传递和神经元可塑性对大脑功能和行为产生负面影响。这些过程 与患有抑郁症的人的情感和认知障碍的高发病率有关。 慢性炎性疾病如自身免疫性、过敏性和全身性炎性疾病。尽管 目前广泛使用的抗炎药物治疗这些疾病，它们在改善炎症反应方面是无效的。 神经行为成分，这与神经炎症的持续性有关，一旦它是 从外围触发。因此，需要找到针对这些疾病的新的治疗方案。 神经炎症过程。人们早就知道麻醉药氯胺酮具有抗炎作用 手术环境中的性能。使用啮齿动物模型，已经表明KET减少炎症反应， 免疫和心因性应激源引发的大脑中的分子，为KET作为一种治疗药物的使用提供了希望。 抗神经炎药。然而，分离，成瘾和镇静作用是 KET为基础的治疗发展的局限性。我们的初步研究表明， KET，（2 R，6 R）-羟基去甲氯胺酮（HNK），缺乏KET的镇静和成瘾作用，具有 在外周给予细菌的小鼠模型中， 脂多糖（LPS）。值得注意的是，我们的初步研究还显示，HNK单独给药 诱导脑中细胞因子IFN-γ的持续转录，提高了HNK介导 这些作用是通过产生这种细胞因子来实现的。本申请将全面评估 HNK的抗神经炎症特性，并在两种模型中测试IFN-g在介导HNK效应中的作用。 使用LPS或细菌上清液（SEA）的外周诱导的神经炎症。具体目标#1， 将描述HNK对CNS炎症过程的剂量、时间和作用，以及确定 HNK诱导的CNS中IFN-γ产生的细胞来源。我们还将评估是否代谢 KET至HNK是KET持续抗神经炎症作用所必需的。在具体目标#2中，我们将利用 缺乏IFN-g的小鼠，以及使用中和抗体对IFN-g进行药理学阻断，以测试其作用。 这种细胞因子在HNK的抗神经炎症作用中的作用。我们还将测试这种细胞因子是否是 HNK在LPS模型中的抗抑郁作用。这一目标还将采用遥测技术来监测活动， 温度和EEG功率带。如果成功，这些探索性/开发性研究将提供 后续R 01应用的基础，以确定HNK诱导的IFN-γ抗神经炎症机制。