Harnessing endogenous cannabinoids for ocular health

描述(申请人提供)：青光眼是两种最常见的失明形式之一，导致全球数百万人失明。眼压升高是青光眼的主要危险因素，大多数青光眼药物都是针对降低眼压的。虽然这些药物有多种种类，但每一种都有局限性，并不是所有的患者都对它们有反应。此外，由于青光眼治疗需要数年甚至数十年的时间，许多患者产生了耐受性，没有治疗选择。在这方面，重要的是要注意到，大麻类药物已被发现对标准疗法耐药的患者有效。1971年，Hepler&Frank的第一篇论文发表，证明了大麻的主要精神活性成分--THC--对眼压有有益的影响。这启动了一项为期40年的系列研究，以了解这种影响的性质，这些研究至今仍在继续。由于生理目标未知，最初的工作集中在THC和相关的植物大麻素上。随着大麻素CB1和CB2受体以及内源性大麻素、2-AG和花生胺的鉴定，这些受体和配体成为大多数后续研究的目标。目前的提议代表了这些研究的下一个合乎逻辑的扩展：1)确定眼内大麻素系统的结构--代谢内源性大麻素(ECB)的酶和产生内源性大麻素的酶。初步结果显示，大麻素信号系统中的大多数“玩家”都出现在前眼。2)我们建议加强内源性信号转导以降低眼压。我们有证据表明，阻断MAGL可以降低眼压，耐人寻味的是，COX阻滞剂扑热息痛通过CB1降低眼压。MAGL是代谢2-AG最重要的酶。重要的是，由于大麻素与神经保护密切相关，我们打算利用内源性大麻素来保护神经元，使用几种眼部病理学模型。这一点很重要，因为高眼压并不是青光眼的唯一危险因素，而且增加了大麻类药物可能不仅用于降低眼压，还用于保护神经元免受青光眼相关损害的可能性。令人惊讶的是，除了CB1的表达外，我们对眼部大麻素知之甚少，尽管已证实大麻素具有降低眼压和作为神经保护剂的潜力。青光眼仍然是一种毁灭性的疾病，影响着数百万人；拟议的研究有可能极大地扩大我们对眼部大麻素信号的了解，并确定与眼睛健康相关的新型药物。

DESCRIPTION (provided by applicant): Glaucoma is one of the two most common forms of blindness, causing millions of cases worldwide. Elevated intraocular pressure (IOP) is the main risk factor and most glaucoma drugs are directed at lowering ocular pressure. While multiple classes of these drugs are available each has limitations and not all patients respond to them. Moreover because glaucoma treatments are required for years or even decades many patients develop tolerance and are left without treatment options. In this context it is important to note that cannabinoids have been found to be effective in patients resistant to standard therapies. 1971 marked the publication of the first work by Hepler & Frank demonstrating that the chief psychoactive ingredient of marijuana - THC - has a salutary effect on intraocular pressure (IOP). This set in motion a 40-year series of studies to learn the nature of this effect, studies that continue today. Because the physiological target was unknown, initial work focused on THC and related phytocannabinoids. With the identification of the cannabinoid CB1 and CB2 receptors and endocannabinoids, 2-AG and anandamide, these receptors and ligands became the target of most subsequent studies. The current proposal represents the next logical extension of these inquiries: 1) to determine the architecture of the ocular endocannabinoid system -- the enzymes that metabolize the endogenous cannabinoids (eCBs) and the enzymes that produce them. Preliminary results show that most 'players' in the cannabinoid signaling system are present in the anterior eye. 2) We propose to enhance endogenous signaling to reduce IOP. We have evidence that blocking MAGL the enzyme most implicated in metabolizing 2-AG lowers IOP and intriguingly that the COX blocker acetaminophen lowers IOP via CB1. Importantly since cannabinoids are strongly implicated in neuroprotection we intend to 3) harness endocannabinoids to protect neurons using several models of ocular pathology. This is important because elevated IOP is not the only risk factor for glaucoma and raises the possibility that cannabinoids may be engaged not only to reduce IOP but also to protect neurons from damage associated with glaucoma. We know surprisingly little about ocular cannabinoids beyond CB1 expression despite the proven potential of cannabinoids to lower IOP and to serve as neuroprotective agents. Glaucoma remains a devastating disease that affects millions; the proposed research has the potential to greatly expand our knowledge of ocular cannabinoid signaling and to identify novel classes of drugs related to ocular health.