Pigment epithelium-derived factor protects retinal ganglion cells

Abstract

BackgroundRetinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors.ResultsCultured 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.ConclusionWe 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.

AMPA receptor desensitization is the determinant of AMPA receptor mediated excitotoxicity in purified retinal ganglion cells

“…Our RGC cultures isolated from neonatal rats were resistant to this excitotoxic insult, whereas adult RGCs appear to be more susceptible to excitotoxicity (Choi, 1985;Pang et al, 2007). Calcium is very important for early neuronal development such as axonal guidance and neuron maturation and this could explain such differences in these findings.…”

Polarized Secretion of PEDF from Human Embryonic Stem Cell–Derived RPE Promotes Retinal Progenitor Cell Survival

“…[27][28][29][30][31][32] We found that polarized hES-RPE cells expressed much higher levels of PEDF in vitro than nonpolarized hES-RPE cells when evaluated by RT-PCR and Western blot analysis. To further quantify the PEDF secretion among the polarized hES-RPE, polarized fRPE cells and nonpolarized RPE counterparts, we used quantitative ELISA to measure the PEDF level in culture media from different RPE cells normalized to total protein of the cell lysates.…”

Hydrocortisone Stimulates Neurite Outgrowth from Mouse Retinal Explants by Modulating Macroglial Activity

“…Previous studies have shown that single growth factors, including basic fibroblast growth factor (FGF2), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor, pigment epitheliumderived factor (PEDF), and vascular endothelial growth factor-A (VEGFA), were able to enhance RGC survival and/or axon regeneration only in a transient and limited manner in vivo and/or in vitro. [23][24][25][26][27][28][29][30][31] Combinations of growth factors that support both soma survival and axonal regeneration have often generated improved results. BDNF and CNTF together, for example, induced increased axon regeneration, 32 while other studies showed that supplementing growth factors with additional factors such as forskolin or insulin further improved axon regeneration.…”