Cholinergic Drugs For Reversal Of Visual Deficits In Glaucoma

用于逆转青光眼视力缺陷的胆碱能药物

• 批准号: 8466759
• 负责人: RANDY H. KARDON
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466759
• 关键词: Accounting; Acetylcholine; Animal Model; Biological Preservation; Blindness; Bromides; Canis familiaris; Cholinergic Agents; Cholinergic Receptors; Chronic; Data; Development; Diabetes Mellitus; Disease; Electroretinography; Eye; Eye diseases; Glaucoma; Human; Inherited; Ischemia; Ischemic Optic Neuropathy; Measures; Mediating; Nerve Fibers; Optic Disk; Optic Nerve; Oral; Pattern; Physiologic Intraocular Pressure; Pupil light reflex; Recovery; Regulation; Rehabilitation therapy; Retina; Retinal Ganglion Cells; Retinal Vascular Occlusion; Safety; Stress Tests; Testing; Topical application; Veterans; Vision; Visual; base; cholinergic; clinical efficacy; esterase inhibitor; in vivo; prevent; restoration

DESCRIPTION (provided by applicant): Project Summary: The central hypothesis of this proposal is that activation of cholinergic receptors in the retina and in glaucomatous optic nerves can be used as effective neuroprotective and rehabilitative approach to mediate preservation and restoration of visual function in eyes with glaucoma. In our preliminary results we demonstrated that these mechanisms are independent from regulation of intraocular pressure. We will test this hypothesis by using cholinergic drugs in vivo by treating dogs with either topical or oral cholinergic agents that have a hereditary, slowly progressive, angle closure form of glaucoma. The broad long-term objective of this study is to evaluate the clinical efficacy and safety of cholinergic-based therapy to prevent visual loss and restore visual function in a relevant large animal model (primary canine glaucoma), which is characterized by chronic elevation of intraocular pressure and progressive retinal ganglion cell loss over the course of several years, similar to human glaucoma. Our specific aims, supported by preliminary data in dogs with a spontaneous form of glaucoma similar to humans, seek to show that topical application of an acetylcholine esterase inhibitor (demecarium bromide) and an oral cholinergic agent (citicholine) are associated with recovery of optic nerve function measured by pattern electroretinography (PERG) and the pupil light reflex, independent of intraocular pressure (IOP) regulation. Pilot data also shows demecarium bromide treatment prevents development of optic nerve head cupping (glaucomatous structural damage). We have also developed provocative intraocular pressure stress tests which reveal early functional deficits in PERG and pupil light reflex (PLR) in canine glaucomatous eyes before any structural loss of nerve fiber layer can be detected. Currently, glaucoma and ischemic disorders of the eye - including diabetes, ischemic optic neuropathy and retinal vascular occlusions - account for a significant proportion of blinding ocular diseases in veterans. Accomplishment of the specific aims in this proposal is likely to provide an additional rehabilitative approach for treatment of vision loss in veterans suffering from glaucoma and other forms of ischemia related blinding diseases.

描述（由申请人提供）： 项目摘要：该提案的中心假设是，视网膜和青光眼视神经中胆碱能受体的激活可用作有效的神经保护和康复方法，以介导青光眼患者视觉功能的保存和恢复。在我们的初步结果中，我们证明这些机制独立于眼内压的调节。我们将通过在体内使用胆碱能药物来测试这一假设，方法是用局部或口服胆碱能药物治疗患有遗传性、缓慢进展、闭角型青光眼的狗。本研究的广泛长期目标是评估基于胆碱能的治疗在相关大型动物模型（原发性犬青光眼）中预防视力丧失和恢复视功能的临床疗效和安全性，其特征是眼内压慢性升高。几年内压力和进行性视网膜神经节细胞损失，类似于人类青光眼。我们的具体目标得到了患有与人类相似的自发性青光眼的狗的初步数据的支持，试图证明局部应用乙酰胆碱酯酶抑制剂（地mecarium bromide）和口服胆碱能药物（胞磷胆碱）与视神经的恢复相关通过图形视网膜电图 (PERG) 和瞳孔光反射测量功能，独立于眼压 (IOP) 调节。试验数据还显示，地mecarium溴化物治疗可预防视神经乳头拔罐（青光眼结构损伤）的发展。我们还开发了刺激性眼内压压力测试，在检测到神经纤维层的任何结构性损失之前，可以揭示犬青光眼眼中 PERG 和瞳孔光反射 (PLR) 的早期功能缺陷。目前，青光眼和眼部缺血性疾病（包括糖尿病、缺血性视神经病变和视网膜血管闭塞）在退伍军人致盲性眼病中占很大比例。该提案中具体目标的实现可能会为患有青光眼和其他形式的缺血相关致盲疾病的退伍军人的视力丧失的治疗提供额外的康复方法。