A translational study of neuroinflammatory depression: Understanding mechanism and evaluation of a novel pharmacologic intervention

神经炎症抑郁症的转化研究：了解新型药物干预的机制和评估

• 批准号: 10273563
• 负责人: Christine Delorenzo
• 金额: $ 2.19万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10273563
• 关键词: Aftercare; Anti-Inflammatory Agents; Antidepressive Agents; Astrocytes; Brain; Chronic; Data; Depressed mood; Disease; Disease remission; Enrollment; Evaluation; Functional disorder; Human; Individual; Inflammatory; Intervention; Major Depressive Disorder; Measures; Medicine; Mental Depression; Messenger RNA; Microglia; Morphology; Mus; Neuroglia; Outcome; Outer Mitochondrial Membrane; Participant; Pathology; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Positron-Emission Tomography; Prefrontal Cortex; Proteins; Proxy; Psychiatry; Rodent; Stress; Subgroup; Testing; Wild Type Mouse; antidepressant effect; biological heterogeneity; celecoxib; clinically relevant; depression model; depressive symptoms; disorder subtype; improved; in vivo; inflammatory marker; microPET; mouse model; neuroinflammation; novel; response; social defeat; targeted treatment; translational study

Major depressive disorder (MDD) is one of the most heterogeneous disorders in psychiatry and first line treatments are inadequate for the majority of patients, likely because they do not target an individual’s subtype. Improving our understanding of MDD subtypes will allow us to (1) identify treatments that target subtype-specific pathophysiology and (2) determine which subgroup of MDD patients will best respond to these treatments, thus improving antidepressant outcomes. In a neuroinflammatory subtype, MDD may manifest via chronic neuroinflammation. The translocator protein (TSPO), located on the outer mitochondrial membrane of microglia and astrocytes, is regarded as a marker of this neuroinflammation and can be measured in vivo by positron emission tomography (PET). In support of a neuroinflammatory subtype of MDD, TSPO, measured by PET, was found to be elevated by 30% on average in the prefrontal cortex (PFC) in MDD relative to healthy individuals. Further, we have preliminary data from a repeated social defeat stress mouse model that shows elevated PFC TSPO and other elevated neuroinflammation markers in a subset of ‘depressed’, non-resilient mice, and that this phenotype is reversed by elimination of TSPO expressing glial cells! To parallel this effect in humans, brain- penetrant anti-inflammatory medications such as celecoxib can be used. Celecoxib has antidepressant effects in MDD; however, the observed effect sizes are highly variable, likely reflecting the biological heterogeneity of MDD. We hypothesize that anti-inflammatory treatments such as celecoxib will be most effective in those with the neuroinflammatory subtype of MDD and that the mechanism of antidepressant action is through a reduction of neuroinflammation. We will test these hypotheses in parallel studies in humans in rodents. For the human aim, we will take advantage of an ongoing study of celecoxib efficacy currently being performed at Stony Brook Medicine (PI: Parsey) by recruiting participants who are already being treated with celecoxib (8 weeks, 400mg/day). 53 MDD participants will be enrolled, with 42 expected to complete the study involving TSPO PET imaging before and after treatment. We hypothesize that higher PFC TSPO (as measured by PET) prior to treatment will be correlated with better response to celecoxib and further, that reductions in PFC TSPO will be correlated to depression improvement after adjusting for covariates. In a parallel study in rodents, we hypothesize that PFC TSPO and other CNS inflammation markers in our repeated social defeat stress mouse model of depression will be elevated as measured by microPET, quantitative protein/mRNA level analysis, and reactive microglial morphology, when compared to wild type mice. Further, we hypothesize that elevated PFC TSPO and other neuroinflammatory markers will be reduced after celecoxib treatment. If mouse and human studies do not agree, this suggests that TSPO PET provides a clinically relevant proxy of neuroinflammation. However, if our hypotheses are confirmed, this would validate that TSPO is a marker of the neuroinflammatory MDD subtype and a target of treatment.

重度抑郁症 (MDD) 是精神病学和一线疾病中最具异质性的疾病之一 治疗对于大多数患者来说是不够的，可能是因为它们不针对个体的亚型。 提高我们对 MDD 亚型的理解将使我们能够 (1) 确定针对亚型特异性的治疗方法 病理生理学和 (2) 确定 MDD 患者的哪个亚组对这些治疗反应最好，从而 改善抗抑郁效果。在神经炎症亚型中，MDD 可能通过慢性表现 神经炎症。易位蛋白（TSPO），位于小胶质细胞线粒体外膜上 和星形胶质细胞，被认为是这种神经炎症的标志物，可以通过正电子在体内测量 发射断层扫描（PET）。为了支持 MDD 的神经炎症亚型，通过 PET 测量的 TSPO 研究发现，与健康人相比，重度抑郁症患者的前额皮质 (PFC) 平均升高 30%。 此外，我们从重复的社交失败应激小鼠模型中获得了初步数据，该模型显示 PFC 升高 在“抑郁”、无弹性的小鼠子集中，TSPO 和其他神经炎症标记物升高，并且这 通过消除表达 TSPO 的神经胶质细胞来逆转表型！为了与人类产生类似的效果，大脑 可以使用塞来昔布等渗透性抗炎药物。塞来昔布具有抗抑郁作用 在MDD中；然而，观察到的效应大小变化很大，可能反映了生物异质性 医学博士。我们假设塞来昔布等抗炎治疗对于患有以下疾病的患者最有效 MDD 的神经炎症亚型，抗抑郁作用的机制是通过减少 神经炎症。我们将在人类和啮齿动物身上进行平行研究来检验这些假设。对于人类来说 目标，我们将利用石溪目前正在进行的塞来昔布疗效研究 医学（PI：Parsey），招募已经接受塞来昔布治疗的参与者（8周， 400毫克/天）。将招募 53 名 MDD 参与者，其中 42 名预计将完成涉及 TSPO PET 的研究 治疗前和治疗后的影像学检查。我们假设在 治疗将与塞来昔布的更好反应相关，并且进一步，PFC TSPO 的减少将 调整协变量后与抑郁症改善相关。在一项针对啮齿动物的平行研究中，我们 假设我们反复社交失败应激小鼠中的 PFC TSPO 和其他中枢神经系统炎症标记物 通过 microPET、定量蛋白质/mRNA 水平分析以及 与野生型小鼠相比，反应性小胶质细胞形态。此外，我们假设 PFC 升高 塞来昔布治疗后 TSPO 和其他神经炎症标志物会减少。如果老鼠和人类 虽然研究并不同意，但这表明 TSPO PET 提供了神经炎症的临床相关代理。 然而，如果我们的假设得到证实，这将验证 TSPO 是神经炎症的标志物 MDD 亚型和治疗目标。