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Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy

CBD修复癫痫血脑屏障功能障碍的机制和治疗潜力

基本信息

批准号：
10644405
负责人：
Bjoern Bauer
金额：
$ 22.95万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644405
关键词：
2-arachidonylglycerol Acute Address Animal Model Anticonvulsants Arachidonate 5-Lipoxygenase Automobile Driving Blood - brain barrier anatomy Blood brain barrier dysfunction Blood capillaries CNR1 gene Cannabidiol Cannabinoids Cannabis sativa plant Characteristics Childhood Chronic Clinical Data Endocannabinoids Endothelium Enzymes Epilepsy Extravasation Feedback Functional disorder Generations Glutamates Human Inflammation Inflammatory Knockout Mice Knowledge Link Lipoxygenase Marketing Mediating Medical Mission National Institute of Neurological Disorders and Stroke Neurons Outcome Patients Pharmacology Policies Public Health Rattus Research Science Seizures Signal Transduction Testing Therapeutic Therapeutic Agents United States National Institutes of Health Work cerebral capillary clinical translation cyclooxygenase 2 glutamatergic signaling improved in vivo in vivo Model innovation metabotropic glutamate receptor type 1 mouse model nervous system disorder neurovascular novel therapeutic intervention pre-clinical prevent repaired translational potential

项目摘要

Blood-brain barrier dysfunction is both a cause and consequence of seizures in patients with epilepsy, yet ther- apeutic options to repair barrier dysfunction do not exist. Key characteristics of barrier dysfunction in epilepsy are neurovascular inflammation and barrier leakage, both result from seizure-mediated release of glutamate. Data support that an inflamed and leaky, and thus, dysfunctional barrier contributes to seizure genesis through a pernicious feedback loop that promotes epilepsy progression. However, current therapeutic options to treat epilepsy are largely neuron-centric and do not address barrier dysfunction. In addition, existing antiseizure drugs (ASDs) do not reliably control all seizures, leaving patients with difficult-to-treat epilepsies prone to uncontrolled seizures. We recently discovered that Cannabidiol (CBD) mitigates barrier dysfunction in epilepsy. We also found that CBD blocks glutamate-mediated barrier leakage in isolated capillaries and repairs seizure-induced barrier dysfunction in vivo. These findings suggest that CBD has the potential to block the feedback signaling that drives barrier dysfunction and seizure progression in epilepsy. However, data that support the use of CBD to repair barrier dysfunction in epilepsy are not available. This knowledge gap represents a critical unmet need that pre- vents us from achieving therapeutic advances for patients with epilepsy. The overall objective in this application is to define the mechanistic link between cannabinoid signaling and barrier dysfunction to explain observed CBD effects and to evaluate CBD as therapeutic agent to repair barrier dysfunction in epilepsy. Based on preliminary data the central hypothesis of this project is that CBD repairs barrier dysfunction thereby lowering seizure burden in epilepsy. The rationale for the proposed research is that its successful completion will provide mechanistic and preclinical data supporting future research for the clinical translation of CBD to treat patients with epilepsy. The hypothesis will be tested by pursuing two specific aims: 1) Describe cannabinoid signaling in glutamate- mediated barrier dysfunction and 2) Evaluate CBD for its potential to repair barrier dysfunction in epilepsy. Under Aim 1, we will describe key mechanistic steps between cannabinoid signaling and glutamate-mediated barrier dysfunction by using brain capillaries isolated from knockout mouse models. We will verify these signaling steps in isolated human brain capillaries. Under Aim 2, we will evaluate the therapeutic benefit of CBD on seizure- mediated neurovascular inflammation, barrier leakage, and seizure burden in chronic epileptic rats. The pro- posed research is innovative, because it focuses on a thus far unaddressed topic: cannabinoid signaling at the blood-brain barrier and CBD as therapeutic agent to repair barrier dysfunction and reduce seizures in epilepsy. The proposed research is significant because it holds the promise of a novel therapeutic approach to repair barrier dysfunction that has translational potential to advance treatment of patients with epilepsy and other sei- zure disorders with underlying barrier dysfunction.

血脑屏障功能障碍既是癫痫患者癫痫发作的原因，也是其后果，但修复屏障功能障碍的治疗选择并不存在。癫痫屏障功能障碍的关键特征神经血管炎症和屏障渗漏都是由癫痫介导的谷氨酸释放引起的。数据表明，发炎、渗漏以及功能障碍的屏障通过以下方式导致癫痫发作：促进癫痫进展的有害反馈循环。然而，目前的治疗选择癫痫主要以神经元为中心，不能解决屏障功能障碍。此外，现有的抗惊厥药物（自闭症谱系障碍）不能可靠地控制所有癫痫发作，导致难以治疗的癫痫患者容易失控癫痫发作。我们最近发现大麻二酚（CBD）可以减轻癫痫的屏障功能障碍。我们还发现 CBD 可以阻止孤立毛细血管中谷氨酸介导的屏障渗漏并修复癫痫引起的屏障体内功能失调。这些发现表明 CBD 有可能阻止驱动的反馈信号屏障功能障碍和癫痫发作进展。然而，数据支持使用 CBD 来修复癫痫的屏障功能障碍尚不可用。这种知识差距代表了一个未满足的关键需求使我们无法在癫痫患者的治疗方面取得进展。本申请的总体目标是定义大麻素信号传导和屏障功能障碍之间的机制联系，以解释观察到的 CBD 效果并评估 CBD 作为修复癫痫屏障功能障碍的治疗剂。根据初步数据该项目的中心假设是 CBD 修复屏障功能障碍，从而降低癫痫发作负担在癫痫病中。拟议研究的基本原理是，其成功完成将提供机制以及支持 CBD 临床转化治疗癫痫患者的未来研究的临床前数据。该假设将通过追求两个具体目标来检验：1）描述谷氨酸中的大麻素信号传导介导的屏障功能障碍；2) 评估 CBD 修复癫痫屏障功能障碍的潜力。在下面目标 1，我们将描述大麻素信号传导和谷氨酸介导的屏障之间的关键机制步骤通过使用从基因敲除小鼠模型中分离出的脑毛细血管来研究功能障碍。我们将验证这些信号步骤在孤立的人脑毛细血管中。在目标 2 下，我们将评估 CBD 对癫痫发作的治疗效果介导慢性癫痫大鼠的神经血管炎症、屏障渗漏和癫痫发作负担。亲所提出的研究具有创新性，因为它关注的是迄今为止尚未解决的主题：大麻素信号传导血脑屏障和 CBD 作为治疗剂修复屏障功能障碍并减少癫痫发作。拟议的研究意义重大，因为它有望提供一种新的修复治疗方法屏障功能障碍具有促进癫痫和其他疾病患者治疗的转化潜力具有潜在屏障功能障碍的疾病。