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首页> 外文学位 >Use of sigma receptor ligands to prevent retinal ganglion cell apoptosis characteristic of diabetic retinopathy.
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Use of sigma receptor ligands to prevent retinal ganglion cell apoptosis characteristic of diabetic retinopathy.

机译：σ受体配体的使用防止糖尿病性视网膜病特征性的视网膜神经节细胞凋亡。

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摘要

The purpose of these studies was to evaluate the potential use of σR ligands, particularly those that bind specifically to σR1, as neuroprotective agents in the treatment of RGC apoptosis characteristic of diabetic retinopathy. RGCs die very shortly after the onset of diabetes. This death of RGCs is mediated by overstimulation of the NMDA receptor by excessive glutamate and possibly homocysteine. The toxic effect of glutamate on retina, particularly RGCs, is well established; however, little is known about the effects of elevated homocysteine on RGCs. In this study it was speculated that increased intravitreal concentrations of homocysteine would trigger death of neurons in the RGC layer. The data indicate that exposure to high levels of homocysteine kills neurons of the ganglion cell layer and that the cells die via an apoptotic mechanism.; To determine whether RGCs die by apoptosis in the STZ-induced diabetic mouse, C57BL/6 mice (3 wks) were made diabetic using STZ. Age-matched, non-injected C57BL/6 mice were maintained as controls. Diabetic and age-matched control mice were sacrificed at varying timepoints post-onset of diabetes and eyes examined systematically for evidence of RGC death.; RGC-5 cells were used to: (1) determine whether acute exposure of RGCs to high levels of homocysteine is toxic in vitro, (2) establish whether this toxicity occurs via activation of NMDA receptors, and (3) determine whether σR ligands, which are neuroprotective through modulation of NMDA receptors, can prevent this apoptosis. The cells were exposed to D, L-homocysteine or L-glutamate (1 mM) in the presence or absence of MK-801, NBQX, nifedipine, (+)-PTZ, or haloperidol at varying concentrations. The data suggest that acute exposure to 1 mM homocysteine or glutamate induces death of cultured RGCs, and this death is mediated via activation of NMDA receptors. The σR1-selective ligand PTZ may prevent the homocysteine and glutamate-induced RGC death.; Taken together, these studies suggest that RGCs die very early in the course of diabetes in the STZ-diabetic mouse. This death of RGCs is mediated by overstimulation of the NMDA subtype of glutamate receptor by elevated levels of glutamate as well as homocysteine. Treatment with MK-801 and PTZ is neuroprotective against RGC death both in vitro and in vivo. (Abstract shortened by UMI.)
机译：这些研究的目的是评估σR配体（特别是那些与σR1特异性结合的配体）作为神经保护剂在糖尿病性视网膜病变的RGC细胞凋亡治疗中的潜在用途。 RGC在糖尿病发作后不久死亡。 RGC的这种死亡是由过量的谷氨酸和可能的同型半胱氨酸过度刺激NMDA受体介导的。谷氨酸对视网膜，特别是RGC的毒性作用是公认的。然而，关于高半胱氨酸升高对RGCs的影响知之甚少。在这项研究中，推测玻璃体内高半胱氨酸浓度的增加会触发RGC层中神经元的死亡。数据表明，暴露于高水平的半胱氨酸会杀死神经节细胞层的神经元，并且这些细胞会通过凋亡机制死亡。为了确定RGC是否在STZ诱导的糖尿病小鼠中通过细胞凋亡而死亡，使用STZ使C57BL / 6小鼠（3周）成为糖尿病。保持年龄匹配的，未注射的C57BL / 6小鼠作为对照。在糖尿病发作后的不同时间点处处死糖尿病和年龄匹配的对照小鼠，并系统地检查眼睛以寻找RGC死亡的证据。 RGC-5细胞用于：（1）确定RGC暴露于高水平同型半胱氨酸是否在体外具有毒性（斜体），（2）确定这种毒性是否通过激活NMDA受体而发生，和（ 3）确定通过调节NMDA受体具有神经保护作用的σR配体是否可以防止这种凋亡。在存在或不存在不同浓度的MK-801，NBQX，硝苯地平，（+）-PTZ或氟哌啶醇的情况下，将细胞暴露于D，L-高半胱氨酸或L-谷氨酸（1 mM）。数据表明，急性暴露于1 mM同型半胱氨酸或谷氨酸会诱导培养的RGC死亡，而这种死亡是通过激活NMDA受体介导的。 σR1选择性配体PTZ可以防止高半胱氨酸和谷氨酸诱导的RGC死亡。综上所述，这些研究表明，RGC在STZ糖尿病小鼠的糖尿病过程中非常早地死亡。 RGC的这种死亡是由谷氨酸和同型半胱氨酸水平升高对谷氨酸受体的NMDA亚型的过度刺激介导的。 MK-801和PTZ的治疗对RGC死亡具有神经保护作用，无论是在体外还是在体内。 （摘要由UMI缩短。）

著录项

  • 作者

    Martin, Pamela Moore.;

  • 作者单位

    Medical College of Georgia.;

  • 授予单位 Medical College of Georgia.;
  • 学科 Biology Cell.; Biology Anatomy.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;生物形态学;病理学;
  • 关键词

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