Cui Q, Harvey A R
Department of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth, Australia.
J Neurosci. 1995 Dec;15(12):8143-55. doi: 10.1523/JNEUROSCI.15-12-08143.1995.
Removal of the superior colliculus (SC) in neonatal Wistar rats results in a rapid loss of retinal ganglion cells (RGCs). There is an early twofold increase in RGC death 4-8 hr postlesion (PL) followed by a later 10-11-fold increase in pyknosis about 24 hr PL. We have now used neurotrophic factors (BDNF, NT-4/5, NT-3, NGF, LIF), glutamate receptor antagonists (MK-801, DNQX, CNQX), an antioxidant (N-ace-tyl-L-cysteine), and an NOS inhibitor (L-NAME) to determine whether the early and late phases of lesion-induced RGC death involved similar or different mechanisms. Normal and pyknotic nuclei of tectally projecting RGCs were visualized by injecting the left s.c. of 2 d old rats with diamidino yellow (DY). Two days later the injection site was removed. In most rats, right eyes were injected with factors immediately after the s.c. ablation. Rats were perfused either 6 or 24 hr PL. In the latter group a second intravitreal injection of the appropriate factor was sometimes made 12 hr PL. NT- 4/5 and BDNF significantly decreased RGC pyknosis 6 and 24 hr PL, whereas NT-3 was only protective 6 hr PL. LIF slightly reduced RGC death 24 hr PL, but NGF had no influence on RGC survival at either time point. NT-4/5 also reduced the rate of naturally occurring RGC death. MK-801, DNQX, CNQX, N-acetylcysteine, and L-NAME all prevented the early lesion-induced increase in RGC death but had no significant effect on RGC death measured 24 hr PL; none of these factors significantly reduced the rate of naturally occuring RGC death. Cycloheximide, shown previously to reduce RGC pyknosis 24 hr PL, did not prevent RGC death 6 hr PL. The data indicate that there are at least two mechanisms involved in RGC death after neonatal target ablation. The early increase is related to excitotoxic effects mediated by glutamate receptors and involves NOS and the production of free radicals. We found no evidence that RGC death measured 24 hr PL is dependent on these processes, but the later death does require protein synthesis and, most likely, the activation of an endogenous suicide program. NT-4/5 and BDNF protected RGCs from both types of lesion-induced death.
切除新生Wistar大鼠的上丘（SC）会导致视网膜神经节细胞（RGCs）迅速丧失。损伤后4 - 8小时（PL），RGC死亡早期增加两倍，随后在约损伤后24小时，固缩增加10 - 11倍。我们现在使用神经营养因子（BDNF、NT - 4/5、NT - 3、NGF、LIF）、谷氨酸受体拮抗剂（MK - 801、DNQX、CNQX）、一种抗氧化剂（N - 乙酰 - L - 半胱氨酸）和一种一氧化氮合酶抑制剂（L - NAME）来确定损伤诱导的RGC死亡的早期和晚期阶段是否涉及相似或不同的机制。通过给2日龄大鼠的左皮下注射双脒基黄（DY）来观察顶盖投射RGCs的正常和固缩核。两天后移除注射部位。在大多数大鼠中，皮下切除后立即给右眼注射因子。在损伤后6小时或24小时对大鼠进行灌注。在后一组中，有时在损伤后12小时进行第二次玻璃体内注射适当的因子。NT - 4/5和BDNF在损伤后6小时和24小时显著降低RGC固缩，而NT - 3仅在损伤后6小时具有保护作用。LIF在损伤后24小时略微降低RGC死亡，但NGF在两个时间点对RGC存活均无影响。NT - 4/5也降低了自然发生的RGC死亡率。MK - 801、DNQX、CNQX、N - 乙酰半胱氨酸和L - NAME均阻止了损伤诱导的RGC死亡早期增加，但对损伤后24小时测量的RGC死亡无显著影响；这些因子均未显著降低自然发生的RGC死亡率。环己酰亚胺先前显示可降低损伤后24小时的RGC固缩，但不能阻止损伤后6小时的RGC死亡。数据表明，新生动物靶标切除后RGC死亡至少涉及两种机制。早期增加与谷氨酸受体介导的兴奋性毒性作用有关，涉及一氧化氮合酶和自由基的产生。我们没有发现证据表明损伤后24小时测量的RGC死亡依赖于这些过程，但后期死亡确实需要蛋白质合成，并且很可能需要激活内源性自杀程序。NT - 4/5和BDNF保护RGCs免受两种类型的损伤诱导死亡。
