Cholinergic Drugs For Reversal Of Visual Deficits In Glaucoma

描述(由申请人提供)： 项目概述：该方案的中心假设是，激活视网膜和青光眼视神经中的胆碱能受体可以作为有效的神经保护和康复途径，介导青光眼患者视觉功能的保护和恢复。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。我们将通过使用体内胆碱能药物来验证这一假设，方法是局部或口服胆碱能药物治疗患有遗传性、缓慢进行性、闭角型青光眼的狗。这项研究的长期目标是评估以胆碱能为基础的治疗在相关大型动物模型(原发犬青光眼)中预防视力丧失和恢复视功能的临床有效性和安全性，该模型的特征是多年慢性眼压升高和进行性视网膜神经节细胞丢失，类似于人类青光眼。我们的具体目标得到了与人类相似的自发性青光眼狗的初步数据的支持，试图表明局部应用乙酰胆碱酯酶抑制剂(溴化脱氧胆碱)和口服胆碱能药物(胞磷胆碱)与模式视网膜电图(PERG)测量的视神经功能恢复和瞳孔光反射有关，与眼压(IOP)调节无关。试点数据还表明，溴化粪便治疗可以防止视神经头部拔罐(青光眼结构性损害)的发展。我们还开发了刺激性眼压压力测试，在检测到神经纤维层的任何结构性丢失之前，我们还开发出了刺激性眼压测试，该测试揭示了狗青光眼的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阻塞--在退伍军人致盲疾病中占相当大的比例。这项提案的具体目标的实现可能会为治疗患有青光眼和其他形式的缺血致盲疾病的退伍军人提供另一种康复方法。

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.