Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany.
Clin Exp Ophthalmol. 2011 Aug;39(6):545-54. doi: 10.1111/j.1442-9071.2010.02486.x. Epub 2011 Feb 23.
Apoptosis is a major mechanism of cell death in glutamate-induced excitotoxicity and caspases as the executors of apoptosis play an important role in the development of various central nervous system and eye diseases. We studied the involvement of certain caspases in excitotoxic retinal ganglion cell death, which was experimentally induced in Brown Norway Rats by application of the glutamate receptor agonist N-methyl-D-aspartate (NMDA).
Animals were injected intravitreally with one of six caspase inhibitors (against caspases 1, 3, 4, 6, 8 and 9). Seven hours later, NMDA or phosphate-buffered saline as a control was injected intravitreally into the respective eyes. The neuroprotective potential against NMDA toxicity was assessed by retinal ganglion cell quantification. Additionally, wholemount TUNEL was performed.
Statistical analysis revealed significant neuroprotective effects for the inhibitors of caspases 3, 6, 8 and 9, but not for those of caspases 1 and 4. The inhibitors of caspases 6 and 9 showed greater neuroprotective potential than those of caspases 3 and 8, although cell death was not entirely averted in any case. Results of ganglion cell counts were confirmed for the most pronounced treatment groups using wholemount TUNEL.
Excitotoxic retinal ganglion cell death after NMDA injection is mediated mainly through apoptosis, whereby extrinsic as well as intrinsic pathways of caspase activation play a role.
细胞凋亡是谷氨酸诱导的兴奋毒性中细胞死亡的主要机制，而半胱天冬酶作为凋亡的执行者在各种中枢神经系统和眼部疾病的发展中起着重要作用。我们研究了某些半胱天冬酶在兴奋性视网膜神经节细胞死亡中的作用，这种死亡是通过向棕色挪威大鼠眼内注射谷氨酸受体激动剂 N-甲基-D-天冬氨酸（NMDA）来实验性诱导的。
动物经玻璃体内注射六种半胱天冬酶抑制剂（针对半胱天冬酶 1、3、4、6、8 和 9）之一。7 小时后，将 NMDA 或磷酸盐缓冲盐水（作为对照）注射到相应的眼睛内。通过视网膜神经节细胞计数评估对 NMDA 毒性的神经保护潜力。此外，还进行了全视网膜 TUNEL 检测。
统计分析显示，半胱天冬酶 3、6、8 和 9 的抑制剂具有显著的神经保护作用，但半胱天冬酶 1 和 4 的抑制剂则没有。半胱天冬酶 6 和 9 的抑制剂比半胱天冬酶 3 和 8 的抑制剂具有更大的神经保护潜力，尽管在任何情况下都不能完全避免细胞死亡。使用全视网膜 TUNEL 对最明显的治疗组进行了神经节细胞计数结果的验证。
NMDA 注射后兴奋性视网膜神经节细胞死亡主要通过细胞凋亡介导，其中外源性和内源性半胱天冬酶激活途径均发挥作用。
