Study on IOP-independent glaucoma treatment and pathogenetic mechanisms of glaucomatous optic neuropathy

我们首先建立了两种青光眼视神经病变的实验模型：一种是前房内注射印度墨水，然后激光照射到房角，另一种是用夹子直接损伤视神经。利用该模型，研究了几种药物对青光眼视神经病变可能的神经保护作用。非竞争性NMDA受体拮抗剂T-588、他克莫司和倍他洛尔对该模型均显示出神经保护作用，并通过视网膜神经节细胞计数、组织病理学和视网膜电图测量证实了这一点。这些结果表明，通过药物修饰凋亡过程的IOP非依赖性青光眼治疗的可能性。另一种视网膜神经节细胞凋亡的大鼠模型是通过血栓形成和视网膜动脉再灌注来建立的。该模型中观察到时间依赖性的凋亡反应，表明该模型可用于青光眼视神经病变的研究。我们在临床环境中研究青光眼视神经病变发生和进展的IOP非依赖性因素。多变量分析表明，几个IOP独立的因素，如视盘出血，视乳头周围萎缩和异常的眼眶血流动力学与青光眼性视神经病变的进展。钙通道阻滞剂治疗与视神经病变的良好预后相关。这些结果表明，除了目前使用的眼部扩张疗法外，有可能出现全新的青光眼治疗方式。

We first established two experimental models of glaucomatous optic neuropathy: one by intracameral Indian ink injection followed by laser irradiation to the chamber angle and the other by direct optic nerve damage with a clip. Using the models, several kinds of drugs were investigated in terms of possible neuroprotective effect on glaucomatous.optic neuropathy. Noncompetitive NMDA receptor antagonists, T-588, tacrolimus and betaxolol successfully showed neuroprotective effects on the models, which were confirmed by retinal ganglion cell counts, histopathology and electroretinogram measurement. These results suggest the possibility of IOP-independent glaucoma therapy by pharmacological modification of the apoptotic process.Another rat model for retinal ganglion cell apoptosis was created by thrombosis formation and reperfusion of the retinal arteries. Time-dependent apoptotic reaction was observed in the model, suggesting that the model might be used for investigation of glaucomatous optic neuropathy.We investigated lOP-independent factors for development and progression of glaucomatous optic neuropathy in a clinical setting. A multivariate analysis demonstrated several lOP-independent factors such as optic disc hemorrhage, peripapillary atrophy and abnormal orbital hemodynamics were associated with progression of glaucomatous optic neuropathy. Calcium-channel blocker treatment was associated with favorable prognosis of optic neuropathy.These results indicate the possibility of totally new treatment modalities for glaucoma other than currently used ocular hypotensive therapy.