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PN Moore, MS Ola, N Agarwal, V Ganapathy, SB Smith; Sigma Receptor (R) Ligands Prevent Apoptotic Retinal Ganglion Cell (RGC) Death Induced by Homocysteine (Hcy) & Glutamate (Glu) . Invest. Ophthalmol. Vis. Sci. 2002;43(13):749.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In diabetic retinopathy, RGCs die by apoptosis within the first 2 years of disease onset. Glu levels are elevated significantly in the vitreous of diabetic patients. The RGC death is thought to occur via overstimulation of the NMDA receptor. Hcy, an excitatory amino acid and homolog of cysteine, is elevated also in diabetes. Previously, we showed that Hcy, like Glu, is toxic to RGCs in vivo. In the present study, we asked whether Hcy is toxic to RGCs in vitro and whether σR1 ligands, which are neuroprotective through modulation of NMDA-receptors, can prevent this apoptosis. Methods: Cultured rat RGC-5 cells were exposed to 1 mM D, L- Hcy-thiolactone or L-Glu for 24 or 48 h. The expression of mRNA encoding σR1 was determined by semiquantitative RT-PCR. Cells were cultured also on chamber slides and upon differentiation were exposed for 24 h to medium containing either 1 mM D, L- Hcy-thiolactone or L-Glu in the presence or absence of (+)-pentazocine (a σR1 ligand), haloperidol, or MK-801 (an NMDA antagonist) [3 and 10 µM]. Fixed cells were subjected to the TUNEL assay. Results: RT-PCR established that σR1 expression in RGC-5 cells is not altered by exposure to high levels of Hcy or Glu, suggesting that σR1 may be an available therapeutic target to prevent the toxic effects of these excitatory amino acids. Exposure to 1 mM Hcy or Glu resulted in a significant increase (∼6 and 10-fold, respectively) in the number of TUNEL-positive RGC-5 cells. Preincubation of the cells with (+)-pentazocine, haloperidol or (+)-MK-801 attenuated by ∼80-90% the Hcy- and Glu-induced apoptosis. Conclusion: Neuroprotection against Hcy and Glu-induced RGC death was afforded by treatment with (+)-pentazocine and haloperidol. Neuroprotective effects were also conferred by similar treatment with (+)-MK-801, suggesting that Hcy-induced RGC death, like Glu-induced death, may be mediated via activation of NMDA receptors.
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