Chaudhary P, Ahmed F, Quebada P, Sharma S C
Department of Ophthalmology/Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
Brain Res Mol Brain Res. 1999 Apr 6;67(1):36-45. doi: 10.1016/s0169-328x(99)00032-7.
Retinal ganglion cells die by apoptosis following axotomy. The molecular mechanisms of the retinal ganglion cell death are not well understood. In the present study using RT-PCR and in situ hybridization techniques we demonstrated that levels of mRNA for Bcl-2 and Bcl-x decreased after axotomy. Bax levels remained high until 4 days after axotomy, decreased by day 7 and remained low up to day 10. CPP32 levels increased at day 7 and remained high after optic nerve cut. We studied whether inhibitors of CPP32/caspase would save the axotomy induced ganglion cell death. DEVD-CHO (Ac-Asp-Glu-Val-aspartic acid aldehyde) and DEVD-FMK (Z-Asp-Glu-Val-Asp-FMK), caspase inhibitors, when administered intraocularly at the time of optic nerve cut, at days 3 and 7 protect about 30-35% the ganglion cells from death. We further demonstrated that the number of reactive microglia decrease in the retina when the inhibitors were given as compared with retina where no inhibitors were given. The present data offers new avenues for studying the complex interactions between the retinal ganglion cell death and the activation of resident microglia/macrophages.
视网膜神经节细胞在轴突切断后通过凋亡死亡。视网膜神经节细胞死亡的分子机制尚未完全清楚。在本研究中，我们使用逆转录聚合酶链反应（RT-PCR）和原位杂交技术证明，轴突切断后Bcl-2和Bcl-x的mRNA水平降低。Bax水平在轴突切断后4天内一直保持较高，到第7天下降，直到第10天一直保持较低水平。CPP32水平在第7天升高，视神经切断后一直保持较高水平。我们研究了CPP32/半胱天冬酶抑制剂是否能挽救轴突切断诱导的神经节细胞死亡。半胱天冬酶抑制剂DEVD-CHO（乙酰天冬氨酸-谷氨酸-缬氨酸-天冬氨酸醛）和DEVD-FMK（Z-天冬氨酸-谷氨酸-缬氨酸-天冬氨酸-氟甲基酮）在视神经切断时、第3天和第7天眼内给药时，可保护约30%-35%的神经节细胞免于死亡。我们进一步证明，与未给予抑制剂的视网膜相比，给予抑制剂时视网膜中反应性小胶质细胞的数量减少。本研究数据为研究视网膜神经节细胞死亡与驻留小胶质细胞/巨噬细胞激活之间的复杂相互作用提供了新的途径。
