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: 10413981
• 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/10413981
• 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; Conflict (Psychology); 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; 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; Receptor Inhibition; Reporting; Rewards; Signal Transduction; Signaling Protein; Spinal; 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; neuroinflammation; pain behavior; pain model; pain patient; pain reduction; pain symptom; preclinical study; radioligand; relating to nervous system; 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.

在美国，数百万人患有慢性疼痛和共病抑郁症， 使人衰弱且管理复杂的条件。缺乏安全有效的 这些疾病的治疗方法是我们对可行靶点的有限知识。疼痛的临床前模型已经显示 小胶质细胞和星形胶质细胞在疼痛和抑郁的建立和/或维持中起关键作用， 行为。此外，慢性下腰痛（cLBP）患者表现出“疼痛相关”， “抑郁症相关”的神经胶质标记物18 kDa转运蛋白（TSPO）水平升高，表明 疼痛和抑郁症状可能由神经炎症机制介导/维持 在这项提案中，我们将研究大麻二酚（CBD），主要的中枢和外周活性， 大麻植物中的一种非毒性化合物，对cLBP患者具有抗神经炎症作用 患有轻度到中度抑郁症在动物中，CBD通过一种新的途径诱导镇痛和抗抑郁作用。 复杂的药理学，包括大麻素受体的刺激和前- 神经胶质细胞中的炎症通路。这些临床前研究和我们的观察结果将神经炎症 cLBP中的疼痛和共病抑郁症状，表明CBD可以减少疼痛和抑郁 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可能使纹状体功能减退正常化， 最近，一个研究小组利用功能性磁共振成像技术， （fMRI）。由于其所谓的对纹状体生理学的影响，我们因此假设次要的 CBD的作用机制可能是减少纹状体功能障碍。 我们将进行一项随机、双盲、双臂机制试验，以评估CBD的作用（n = 10）。 40)和安慰剂（n = 40）在轻度至中度抑郁的cLBP患者中，使用积分正电子 发射断层扫描/磁共振成像（PET/MRI）扫描。使用集成PET/MRI将 使我们能够同时评估神经炎症（使用[11 C] PBR 28，一种第二代放射性配体，用于 TSPO）和纹状体功能（使用货币激励延迟任务，这是一项经过验证的功能磁共振成像任务， 对奖励和损失的行为和神经反应）。在我们的机械试验中，我们将使用EPIDIOLEX®， FDA批准的产品，含有已知和恒定剂量的纯化CBD。我们已经抓到一个 IND使用[11 C] PBR 28 PET/MRI测试EPIDIOLEX®在cLBP中的作用，初步数据支持我们的研究。 假设通过研究CBD的神经和神经免疫反应，这项研究将推动我们的研究。 了解这种药物的作用机制，并帮助我们了解哪些条件可能受益 最多的是它的使用。更广泛地说，我们的研究将测试调节神经炎症是否可行， 治疗疼痛和抑郁症的好方法