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

血脑屏障功能障碍是癫痫患者癫痫发作的原因和后果，但- 目前尚不存在修复屏障功能障碍的治疗选择。癫痫患者屏障功能障碍的主要特征 神经血管炎症和屏障渗漏，两者都是由癫痫介导的谷氨酸释放引起的。 数据支持炎症和渗漏，因此，功能障碍通过以下途径促进癫痫的发生 一个有害的反馈循环，促进癫痫的进展。然而，目前治疗的选择 癫痫主要是以神经元为中心的，并不涉及屏障功能障碍。此外，现有的抗癫痫药物 自闭症(ASDS)不能可靠地控制所有癫痫发作，使难治性癫痫患者容易失控 癫痫发作。我们最近发现，大麻二醇(CBD)可减轻癫痫患者的屏障功能障碍。我们还发现 CBD阻断谷氨酸介导的毛细血管屏障渗漏和修复癫痫诱导的屏障 体内功能障碍。这些发现表明，CBD有可能阻止驱动 癫痫中的屏障功能障碍和癫痫发作进展。但是，支持使用CBD进行修复的数据 癫痫的屏障功能障碍是不可用的。这一知识差距代表着一种关键的未得到满足的需求，即 使我们无法在癫痫患者的治疗方面取得进展。本应用程序的总体目标是 是确定大麻素信号和屏障功能障碍之间的机制联系，以解释观察到的CBD 并评价CBD对癫痫患者屏障功能障碍的修复作用。基于初步的 数据：该项目的中心假设是CBD修复屏障功能障碍，从而降低癫痫负担 得了癫痫。拟议研究的理由是，它的成功完成将提供机械 为今后CBD临床翻译治疗癫痫患者的研究提供临床前数据支持。 这一假说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- 介导性屏障功能障碍和2)评估CBD修复癫痫屏障功能障碍的潜力。在……下面 目的1，我们将描述大麻素信号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来的脑毛细血管来实现功能障碍。我们将验证这些信令步骤 在孤立的人脑毛细血管中。在目标2下，我们将评估CBD对癫痫的治疗效果- 慢性癫痫大鼠的神经血管炎症、屏障渗漏和癫痫负担。支持- 提出的研究是创新的，因为它集中在一个迄今尚未解决的主题：大麻素信号在 血脑屏障和CBD作为治疗药物修复屏障功能障碍，减少癫痫发作。 这项拟议的研究意义重大，因为它有望找到一种新的修复方法。 屏障功能障碍具有促进癫痫和其他疾病患者治疗的翻译潜力 伴有潜在屏障功能障碍的Zure障碍。

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.