| 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.)... |
