Pigment epithelium-derived factor protects retinal ganglion cells.
BACKGROUND
Retinal 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.


RESULTS
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 microM). In the presence of 100 microM 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 kappaB (NFkappaB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF.


CONCLUSIONS
We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFkappaB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma.
Pang
Iok-Hou
IH
Alcon Research, Ltd,, 6201 South Freeway, R3-24, Fort Worth, TX 76134, USA. iok-hou.pang@alconlabs.com
Zeng
Hong
H
Fleenor
Debra L
DL
Clark
Abbot F
AF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000008:administration & dosage*; D005901:Glaucoma / Q000473:pathology* / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology*; D015843:Serpins / Q000008:administration & dosage*; D016896:Treatment Outcome; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor