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和结果不存在修复屏障功能障碍的猿类选择。癫痫障碍功能障碍的关键特征是神经血管炎症和屏障泄漏，均由癫痫发作介导的谷氨酸释放引起。数据支持发炎和泄漏，因此，功能失调的障碍通过一个有害的反馈回路，可促进癫痫进展。但是，当前治疗的治疗选择癫痫主要以神经元为中心，并且不能解决障碍功能障碍。此外，现有的抗性药物（ASDS）不能可靠地控制所有癫痫癫痫发作。我们最近发现，大麻二酚（CBD）会缓解癫痫中的屏障功能障碍。我们还发现 CBD阻断了谷氨酸介导的屏障泄漏，并在隔离的毛细血管中泄漏并维修癫痫发作诱导的屏障体内功能障碍。这些发现表明，CBD有可能阻止驱动的反馈信号癫痫的障碍功能障碍和癫痫发作进展。但是，支持使用CBD维修的数据癫痫中的障碍功能障碍不可用。这种知识差距代表了预先未满足的至关重要的需求驱动我们无法为癫痫患者实现治疗进展。此应用程序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械联系，以解释观察到的CBD 效应并评估CBD作为治疗剂，以修复癫痫中的屏障功能障碍。基于初步数据该项目的中心假设是CBD修复屏障功能障碍，从而降低了癫痫发作负担在癫痫中。拟议的研究的理由是，其成功完成将提供机械和临床前数据支持CBD临床翻译的未来研究，以治疗癫痫患者。该假设将通过追求两个具体目的来检验：1）描述谷氨酸 - 介导的屏障功能障碍和2）评估CBD的修复癫痫中屏障功能障碍的潜力。在下面 AIM 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械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的功能障碍。我们将验证这些信号步骤在孤立的人脑毛细管中。在AIM 2下，我们将评估CBD对癫痫发作的治疗益处慢性癫痫大鼠中介导的神经血管炎症，屏障泄漏和癫痫发作负担。专业人士提出的研究具有创新性，因为它侧重于迄今未解决的主题：大麻素信号传导血脑屏障和CBD作为修复屏障功能障碍并减少癫痫发作的治疗剂。拟议的研究很重要，因为它具有一种新颖的治疗方法的承诺具有转化潜力的屏障功能障碍，可以预先治疗癫痫患者和其他诊断患者 ZURE疾病具有潜在的障碍功能障碍。