Cholinergic Drugs For Reversal Of Visual Deficits In Glaucoma

描述（由申请人提供）： 项目摘要：该建议的中心假设是，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，以介导青光眼眼睛的视觉功能的保存和恢复。在我们的初步结果中，我们证明了这些机制独立于眼内压的调节。我们将通过使用胆碱能药物在体内治疗具有遗传性、缓慢进行性、闭角型青光眼的狗，通过局部或口服胆碱能药物来测试这一假设。本研究的广泛长期目标是在相关大型动物模型（原发性犬青光眼）中评价基于胆碱能的治疗预防视力丧失和恢复视功能的临床疗效和安全性，该模型的特征是眼内压慢性升高和数年内进行性视网膜神经节细胞丢失，与人类青光眼相似。我们的具体目标，支持的初步数据，在狗与人类类似的自发性青光眼，试图表明，局部应用乙酰胆碱酯酶抑制剂（地美溴铵）和口服胆碱能药物（Citicholine）与恢复的视神经功能测量模式视网膜电图（PERG）和瞳孔对光反射，独立于眼内压（IOP）的调节。试验数据还显示，地美溴铵治疗可防止视神经乳头杯状（神经性结构损伤）的发展。我们还开发了刺激性眼内压应力测试，其在可以检测到神经纤维层的任何结构性损失之前揭示了犬脑昏迷眼中PERG和瞳孔对光反射（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。实现本提案中的具体目标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提供额外的康复方法。 公共卫生相关性： 项目叙述：由血流和氧气输送减少引起的视网膜和视神经的缺血性损伤通常通过损害眼睛的神经元和相关的神经胶质元件而导致失明。目前，青光眼和眼睛的缺血性疾病-包括糖尿病、缺血性视神经病变和视网膜血管闭塞-在退伍军人群体中占致盲眼病的很大比例。该提案具有很大的相关性，因为它试图证明口服和局部胆碱能药物治疗可以逆转青光眼中的视觉功能障碍，还有助于防止进一步的损失，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提供额外的康复方法。

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. PUBLIC HEALTH RELEVANCE: Project Narrative: Ischemic insults to the retina and optic nerve caused by reduced blood flow and oxygen delivery often lead to blindness by damaging the neurons and associated glial elements of the eye. 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 the veteran population. This proposal has great relevance because it seeks to demonstrate that treatment with oral and topical cholinergic agents can reverse visual dysfunction in glaucoma and also helps prevent further loss, providing an additional rehabilitative approach for treatment of vision loss in veterans suffering from glaucoma and other forms of ischemia related blinding diseases.