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

神经免疫学领域的研究，包括我们小组的工作，已经表明外周和 全身炎症通过几种机制传导到中枢神经系统(CNS)，导致 以细胞因子和其他炎症因子表达增加为特征的神经炎性过程 调解人。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 与罹患以下疾病的人的情绪和认知障碍的高发生率有关 自身免疫性、过敏性和全身性炎症性疾病等慢性炎症性疾病。尽管 目前广泛使用抗炎药物来治疗这些疾病，它们在改善 神经行为成分，它与一旦出现神经炎症的持久性有关 从外围触发。因此，有必要找到针对这些疾病的新的治疗方案。 神经炎性过程。很早就知道麻醉药氯胺酮具有抗炎作用。 在外科环境中的财产。在啮齿动物模型上，KET已经被证明可以减少炎症反应 由免疫和心理应激源触发的大脑中的分子，为KET作为一种 人类使用的抗神经炎药。然而，解离、上瘾和镇静的作用是 KET疗法发展的局限性。我们的初步研究表明，一种 KET，(2R，6R)-羟基去甲氯胺酮(HNK)缺乏KET的镇静和成瘾作用，具有 细菌外周给药小鼠模型的强大抗神经炎作用 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 诱导细胞因子干扰素-g在大脑中持续转录，增加了HNK介导的可能性 这些效应是通过产生这种细胞因子来实现的。本申请将全面评估 HNK的抗神经炎作用及干扰素-g在两种模型中的作用 用脂多糖或细菌超氧化物歧化酶(SEA)外周注射诱导神经炎症。在具体目标#1中，我们 将表征HNK的剂量、时间和对中枢神经系统炎症过程的影响，以及确定 HNK诱导中枢神经系统产生干扰素-g的细胞来源。我们还将评估新陈代谢是否 KET对HNK的持续抗神经炎作用是必需的。在具体目标2中，我们将利用 缺乏干扰素-g的小鼠，以及使用中和抗体药理阻断干扰素-g的小鼠，以测试其作用 这种细胞因子在HNK的抗神经炎作用中的作用。我们还将测试这种细胞因子是否需要 HNK在脂多糖模型中的抗抑郁作用。这个目标还将使用遥测来监测活动， 体温和脑电功率频段。如果成功，这些探索性/发展性研究将提供 为后续R01应用以确定HNK诱导的干扰素-g抗神经炎机制奠定了基础。

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.