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Abstract #8996 Published in IGR 5-2
Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells
Aoun P; Simpkins JW; Agarwal NInvestigative Ophthalmology and Visual Science 2003; 44: 2999-3004
PURPOSE: The peroxisome proliferator-activated receptor-gamma (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-gamma agonists, 15-deoxy-D(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone were used. RGC-5 cells were incubated with either of the PPAR-gamma 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 1-5 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-gamma 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-gamma-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.
Dr. P. Aoun, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Classification:
11.8 Neuroprotection (Part of: 11 Medical treatment)