Anti-inflammatory effect of pigment epithelium-derived factor in DBA/2J mice.
OBJECTIVE
Glaucoma is the second leading cause of blindness. The ultimate cause of vision loss in glaucoma is thought to be retinal ganglion cell (RGC) death. Neuroprotection of RGC is therefore an important goal of glaucoma therapy. Several lines of evidence suggest that pigment epithelium derived factor (PEDF) is a potent anti-angiogenic, neuroprotective, and anti-inflammatory factor for neurons. In this study, we examined the potential role of PEDF in protection of RGC in the DBA/2J mouse, an animal model of inherited glaucoma.


METHODS
DBA/2J mice at two months of age were transfected intravitreally with adeno-associated virus (AAV)-PEDF or AAV-green fluorescent protein (AAV-GFP). RGC and nerve fiber layer protection were evaluated in retinal cross sections. Biochemical alterations in the retinas of DBA/2J mice in response to intravitreal transfection of PEDF were also examined by reverse transcriptase PCR (RT-PCR) and western blot. Cellular localization of PEDF and glial fibrillary acidic protein (GFAP) was determined by immunohistochemistry. Visual acuity was determined by optomotor testing.


RESULTS
PEDF protein levels in the retina and optic nerves of DBA/2J mice declined with age. The expression of tumor necrosis factor (TNF), GFAP, and interleukin-18 (IL-18) increased with age in the retina and optic nerve of DBA/2J mice. Intravitreal PEDF transfection in DBS/2J mice reduced loss of RGC and nerve fiber layer, delayed vision loss, and reduced TNF, IL-18, and GFAP expression in the retina and optic nerve.


CONCLUSIONS
Transduced PEDF potently and efficaciously reduces RGC loss and vision decline in DBA/2J mice, possibly via the reduction of TNF and IL-18, and downregulation of GFAP. The anti-inflammatory effect of PEDF represents a novel approach to the prevention of glaucomatous RGC death.
Zhou
Xiaohong
X
Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Li
Feng
F
Kong
Li
L
Chodosh
James
J
Cao
Wei
W
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005901:Glaucoma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009412:Nerve Fibers / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology; D015843:Serpins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014792:Visual Acuity / Q000187:drug effects; D000099174:Pigment Epithelium-Derived Factor
D000893:Anti-Inflammatory Agents; D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D020382:Interleukin-18; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D000099174:Pigment Epithelium-Derived Factor