Pigment epithelium-derived factor protects retinal ganglion cells

Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC50 = 31 μM). In the presence of 100 μM glutamate, RGC number decreased to 55 ± 4% of control (mean ± SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 ± 4%, n = 60, P < 0.001). PEDF protected against both insults with EC50 values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor κB (NFκB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF.We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFκB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma.Glaucoma, one of the world's leading causes of visual impairment and blindness [1], is characterized by excavation of the optic nerve head and selective apoptotic loss of retinal ganglion cells (RGCs), resulting in a progressive decline in visual function. Elevated intraocular pressure is a major risk factor for the development and progression of glaucoma, although the loss of vision in glaucoma patients does not always correlate with intraocular pressure and lowering pressure sometimes does not completely impede the disease process [2-4]. Clearly, ocular hypertension is not the exclusive cause of glaucomatous retinopathy, and additional mechanisms likely play a role in the degeneration of RGCs. In the past years, several additional mechanisms for glaucomatous optic neuropathy and retinopathy have been proposed, including disrupted retrograde transpo