Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse.
OBJECTIVE
To evaluate the neuroprotective potential of glial cell line-derived neurotrophic factor (GDNF) in the retinal degeneration (rd/rd) mouse model of human retinitis pigmentosa.


METHODS
Subretinal injections of GDNF were made into rd/rd mice at 13 and 17 days of age and electroretinograms (ERGs) recorded at 22 days. Control mice received saline vehicle injections or underwent no procedure. At 23 days of age, retinas from treated and control mice were fixed and processed for wholemount immunohistochemistry using an anti-rod opsin antibody, and rod numbers were estimated using an unbiased stereological systematic random approach. Subsequent to counting, immunolabeled retinas were re-embedded and sectioned in a transverse plane and the numbers of rods recalculated.


RESULTS
Although ERGs could not be recorded from sham-operation or nonsurgical rd/rd mice at 22 days of age, detectable responses (both a- and b-waves) were observed in 4 of 10 GDNF-treated mice. Stereological assessment of immunolabeled rods at 23 days showed that control rd/rd retinas contained 41,880+/-3,890 (mean +/- SEM; n = 6), phosphate-buffered saline (PBS)-injected retinas contained 61,165+/-4,932 (n = 10; P < 0.001 versus control retinas) and GDNF-injected retinas contained 89,232+/-8,033 (n = 10; P < 0.001 versus control retinas, P < 0.002 versus PBS). This increase in rod numbers after GDNF treatment was confirmed by cell counts obtained from frozen sections.


CONCLUSIONS
GDNF exerts both histologic and functional neuroprotective effects on rod photoreceptors in the rd/rd mouse. Thus rescue was demonstrated in an animal model of inherited retinal degeneration in which the gene defect was located within the rods themselves, similar to most forms of human retinitis pigmentosa. GDNF represents a candidate neurotrophic factor for palliating some forms of hereditary human blindness.
Frasson
M
M
Laboratoire de Physiopathologie Rétinienne, Clinique Ophthalmologique, Université Louis Pasteur, Centre Hospitalier Régional Universitaire, Strasbourg, France.
Picaud
S
S
Léveillard
T
T
Simonutti
M
M
Mohand-Said
S
S
Dreyfus
H
H
Hicks
D
D
Sabel
J
J
D000818:Animals; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival; D004596:Electroretinography; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology*; D009457:Neuroglia; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017299:Rod Opsins / Q000378:metabolism
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017299:Rod Opsins