Osborne N N, Ugarte M, Chao M, Chidlow G, Bae J H, Wood J P, Nash M S
Nuffield Laboratory of Ophthalmology, University of Oxford, UK.
Surv Ophthalmol. 1999 Jun;43 Suppl 1:S102-28. doi: 10.1016/s0039-6257(99)00044-2.
Management of glaucoma is directed at the control of intraocular pressure (IOP), yet it is recognized now that increased IOP isjust an important risk factor in glaucoma. Therapy that prevents the death of ganglion cells is the main goal of treatment, but an understanding of the causes of ganglion cell death and precisely how it occurs remains speculative. Present information supports the working hypothesis that ganglion cell death may result from a particular form of ischemia. Support for this view comes from the fact that not all types of retinal ischemia lead to the pathologic findings seen in glaucomatous retinas or to cupping in the optic disk area. Moreover, in animal experiments in which ischemia is caused by elevated IOP, a retinal abnormality similar to that seen in true glaucoma is produced, whereas after occlusion of the carotid arteries a different pattern of damage is found. In ischemia, glutamate is released, and this initiates the death of neurons that contain ionotropic glutamate (NMDA) receptors. Elevated glutamate levels exist in the vitreous humor of patients with glaucoma, and NMDA receptors exist on ganglion cells and a subset of amacrine cells. Experimental studies have shown that a variety of agents can be used to prevent the death of retinal neurons (particularly ganglion cells) induced by ischemia. These agents are generally those that block NMDA receptors to prevent the action of the released glutamate or substances that interfere with the subsequent cycle of events that lead to cell death. The major causes of cell death after activation of NMDA receptors are the influx of calcium into cells and the generation of free radicals. Substances that prevent this cascade of events are, therefore, often found to act as neuroprotective agents. For a substance to have a role as a neuroprotective agent in glaucoma, it would ideally be delivered topically to the eye and used repeatedly. It is, therefore, of interest that betaxolol, a beta-blocker presently used to reduce IOP in humans, also has calcium channel-blocking functions. Moreover, experimental studies show that betaxolol is an efficient neuro protective agent against retinal ischemia in animals, when injected directly into the eye or intraperitoneally.
青光眼的治疗旨在控制眼压（IOP），然而现在人们认识到眼压升高只是青光眼的一个重要危险因素。防止神经节细胞死亡的治疗是主要治疗目标，但对神经节细胞死亡的原因以及确切发生机制仍存在推测。目前的信息支持这样一个工作假设，即神经节细胞死亡可能源于一种特殊形式的缺血。这一观点的依据是，并非所有类型的视网膜缺血都会导致青光眼性视网膜中所见的病理改变或视盘区域的杯状凹陷。此外，在通过升高眼压引起缺血的动物实验中，会产生与真正青光眼相似的视网膜异常，而在颈动脉闭塞后则会发现不同的损伤模式。在缺血状态下，谷氨酸会释放出来，这会引发含有离子型谷氨酸（NMDA）受体的神经元死亡。青光眼患者的玻璃体液中谷氨酸水平升高，神经节细胞和一部分无长突细胞上存在NMDA受体。实验研究表明，多种药物可用于预防缺血诱导的视网膜神经元（尤其是神经节细胞）死亡。这些药物通常是那些阻断NMDA受体以防止释放的谷氨酸发挥作用的药物，或者是干扰导致细胞死亡的后续事件循环的物质。NMDA受体激活后细胞死亡的主要原因是钙流入细胞以及自由基的产生。因此，通常发现能够阻止这一系列事件的物质具有神经保护作用。对于一种物质要在青光眼中发挥神经保护作用，理想情况下它应能局部递送至眼部并可重复使用。因此，目前用于降低人类眼压的β受体阻滞剂倍他洛尔也具有钙通道阻断功能，这一点很有意思。此外，实验研究表明，当直接注入眼内或腹腔内时，倍他洛尔是一种有效的抗动物视网膜缺血的神经保护剂。
