Evaluation of Cannabidiol for Reduction of Brain Neuroinflammation

大麻二酚减少脑神经炎症的评价

• 批准号: 10605299
• 负责人: Jodi Gilman
• 金额: $ 75.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605299
• 关键词: Analgesics; Animals; Anterior; Astrocytes; Beck depression inventory; Behavior; Behavioral; Brain; Brief Pain Inventory; Cannabidiol; Cannabinoids; Cannabis; Chronic low back pain; Clinical Research; Complex; Consumption; Corpus striatum structure; Data; Disease; Dose; Double-Blind Method; Evaluation; Exhibits; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Heterogeneity; Incentives; Individual; Inflammatory; Investigational New Drug Application; Knowledge; Link; MRI Scans; Magnetic Resonance Imaging; Maintenance; Marketing; Measures; Mediating; Mental Depression; Methodology; Microglia; Neuroglia; Neuroimmune; Pain; Pain management; Pathway interactions; Patients; Peripheral; Pharmacology; Physiology; Placebos; Plants; Play; Positron-Emission Tomography; Pre-Clinical Model; Proteins; Randomized; Reaction Time; Reporting; Rewards; Signal Transduction; Signaling Protein; Spinal Cord; Structure; Testing; Thalamic structure; Therapeutic; United States; antidepressant effect; arm; brain circuitry; cannabinoid receptor; chronic pain; cingulate cortex; clinical pain; comorbid depression; comorbidity; depressive behavior; depressive symptoms; drug action; efficacious treatment; financial incentive; glial activation; neural; neuroinflammation; pain behavior; pain model; pain patient; pain reduction; pain symptom; preclinical study; radioligand; response; therapeutic target

Millions of individuals in the United States suffer from chronic pain and co-morbid depression, conditions that are debilitating and complex to manage. A reason for the scarcity of safe and efficacious therapies for these conditions is our limited knowledge of viable targets. Preclinical models of pain have shown that microglia and astrocytes play a key role in the establishment and/or maintenance of pain and depressive behaviors. Additionally, patients with chronic low back pain (cLBP) demonstrate “pain-related” and “depression-related” elevated levels of the glial marker 18kDa translocator protein (TSPO), suggesting that pain and depressive symptoms may be mediated / maintained by neuroinflammatory mechanisms In this proposal, we will study whether cannabidiol (CBD), the primary centrally and peripherally active non-intoxicating compound in the cannabis plant, exerts anti-neuroinflammatory effects in patients with cLBP with mild-to-moderate depression. In animals, CBD induces analgesic and antidepressant effects, via a complex pharmacology that includes the stimulation of cannabinoid receptors and the inhibition of pro- inflammatory pathways in glial cells. These preclinical studies, and our observations linking neuroinflammation to pain and comorbid depressive symptoms in cLBP, indicate that CBD may reduce both pain- and depression- related neuroinflammation in cLBP patients. In addition to exerting possible anti-neuroinflammatory effects, studies in psychiatric patients suggest that CBD might normalize striatal hypofunction, an alteration that our group has also recently linked to depression in cLBP patients using functional magnetic resonance imaging (fMRI). Because of its purported effects as striatal physiology, we thus hypothesize that a secondary mechanism of action of CBD may be to reduce striatal dysfunction. We will conduct a randomized, double-blind, 2-arm mechanistic trial to assess the effects of CBD (n = 40) and placebo (n = 40) in patients with cLBP with mild-to-moderate depression, using integrated positron emission tomography / magnetic resonance imaging (PET/MRI) scans. The use of integrated PET/MRI will allow us to simultaneously evaluate neuroinflammation (using [11C]PBR28, a second-generation radioligand for TSPO) and striatal function (using the Monetary Incentive Delay task, a validated fMRI task that probes behavioral and neural responses to rewards and losses). In our mechanistic trial, we will use EPIDIOLEX®, an FDA-approved product that contains a known and constant dose of purified CBD. We already hold an active IND to test the effects of EPIDIOLEX® in cLBP with [11C]PBR28 PET/MRI, and preliminary data support our hypotheses. By studying the neural and neuroimmune responses to CBD, this study will advance our knowledge about the mechanisms of action of this drug, and help us understand which conditions might benefit the most from its use. More broadly, our study will test whether modulating neuroinflammation is feasible and a promising therapeutic approach for pain and depression.

美国成千上万的人患有慢性疼痛和合并抑郁症， 衰弱且复杂的条件。缺乏安全有效的原因 这些条件的疗法是我们对可行目标的有限了解。临床前疼痛模型已显示 小胶质细胞和星形胶质细胞在疼痛的建立和/或抑郁症中起着关键作用 行为。此外，患有慢性腰痛（CLBP）的患者表现出“与疼痛有关”和 “与抑郁相关”的胶质标记物18KDA易位蛋白（TSPO）的水平升高，表明 疼痛和抑郁症状可以通过神经炎症机制介导 /维持 在此提案中，我们将研究大麻二酚（CBD）是否是中央和周边活动 大麻植物中的无毒性化合物对CLBP患者施加抗神经炎症作用 有轻度到中度的抑郁症。在动物中，CBD通过A诱导镇痛和抗抑郁作用 复杂的药理学，包括刺激大麻素受体和抑制前药理学 神经胶质细胞中的炎症途径。这些临床前研究以及我们与神经炎症联系起来的观察结果 在CLBP中疼痛和合并性抑郁症状，表明CBD可能会减轻疼痛和抑郁症 - CLBP患者的相关神经炎症。除了发挥可能的抗神经炎症作用外， 对精神病患者的研究表明，CBD可能会标准化纹状体功能功能障碍，这是我们的改变 最近还使用功能磁共振成像与CLBP患者的抑郁症相关 （fMRI）。因此，由于其称为纹状体生理的作用，我们因此假设是次要的 CBD的作用机理可能是减少纹状体功能障碍。 我们将进行一项随机，双盲的2臂机械试验，以评估CBD的影响（n = 40）和安慰剂（n = 40）患有轻度至中度抑郁症的患者，使用集成正电子 发射断层扫描 /磁共振成像（PET / MRI）扫描。综合宠物/MRI的使用将 允许我们同时评估神经炎症（使用[11C] PBR28，第二代放射性物体 TSPO）和纹状体功能（使用货币激励延迟任务，这是一个验证的fMRI任务 行为和神经对奖励和损失的反应）。在我们的机械试验中，我们将使用Epidiolex® FDA批准的产品包含已知且恒定剂量的纯化CBD。我们已经活跃了 IND用[11C] PBR28 PET/MRI测试Epidiolex®在CLBP中的效果，并且初步数据支持我们 假设。通过研究神经元和神经免疫性对CBD的反应，这项研究将推动我们的 了解该药物作用机制，并帮助我们了解哪些条件可能受益 最多的使用。更广泛地，我们的研究将测试调节神经炎症是否可行，并且 有希望的疼痛和抑郁症治疗方法。