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Paul Aoun, James W. Simpkins, Neeraj Agarwal; Role of PPAR-γ Ligands In Neuroprotection against Glutamate-Induced Cytotoxicity in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2003;44(7):2999-3004. doi: 10.1167/iovs.02-1060.
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purpose. The peroxisome proliferator-activated receptor-γ (PPAR-γ) is the target of the insulin sensitizing thiazolidinediones (TZDs), a class of drugs used in the treatment of type 2 diabetes mellitus. Glaucoma and other retinal disorders are some of the major complications in diabetes. In the present study, the role that PPAR-γ ligands play in protecting retinal ganglion cells (RGC-5) against glutamate insult was explored.
methods. Transformed rat RGC (RGC-5 cells) and two PPAR-γ agonists, 15-deoxy-d 12,14-prostaglandin J2 (15d-PGJ2) and troglitazone were used. RGC-5 cells were incubated with either of the PPAR-γ ligands and were exposed to either l-glutamic acid or buthionine sulfoximine (BSO). Cell viability was determined with the neutral red dye uptake assay. Levels of PPAR-γ receptor proteins were monitored by immunoblot analysis.
results. Glutamate treatment resulted in RGC-5 cell death, and both 15d-PGJ2 and troglitazone protected the RGC-5 cells from glutamate cytotoxicity. The neuroprotective concentrations of both compounds ranged from approximately 1 to 5 μM. Troglitazone further protected against BSO toxicity, whereas 15d-PGJ2 did not. Glutamate treatment appears to exert its cytotoxicity through oxidative damage, because pretreatment of RGC-5 cells with the antioxidants N-acetyl cysteine (NAC) and thiourea resulted in the reversal of glutamate cytotoxicity. Furthermore, the glutamate effect was not reversed by pretreatment with MK801 or dl-threo-betabenzyloxyaspartate (dl-TBOA), suggesting that glutamate cytotoxicity is not mediated through the NMDA receptor and/or glutamate transporter, respectively. Levels of PPAR-γ receptor protein did not show any appreciable change in response to glutamate exposure, with or without 15d-PGJ2 or troglitazone.
conclusions. Two PPAR-γ ligands, 15d-PGJ2 and troglitazone, protect RGC-5, an established transformed rat retinal ganglion cell line, against glutamate cytotoxicity. The neuroprotective effects of the two compounds appear to be mediated through an antioxidant rather than a PPAR-γ–dependent pathway. These results suggest that PPAR-γ agonists, in addition to improving insulin sensitivity, may also provide a valuable antioxidant benefit that could prove valuable in targeting ocular complications including glaucoma.
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