Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse

PURPOSE. TO evaluate the neuroprotective potential of glial cell line-deriv ed neurotrophic factor (GDNF) in the retinal degeneration (rd/rd) mouse mod el 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 m ice received saline vehicle injections or underwent no procedure. At 23 day s of age, retinas from treated and control mice were fixed anti processed f or wholemount immunohistochemistry using an anti-rod opsin antibody, and ro d numbers were estimated using an unbiased stereological systematic random approach. Subsequent to counting, immunolabeled retinas were re-embedded an d sectioned in a transverse plane and the numbers of rods recalculated. RESULTS. Although ERGs could not be recorded from sham-operation or nonsurg ical rd/rd mice at 22 days of age, detectable responses (both a- and b-wave s) were observed in 4 of 10 GDNF-treated mice. Stereological assessment of immunolabeled rods at 23 days showed that control rd/rd retinas contained 4 1,880 +/- 3,890 (mean +/- SEM; n = 6), phosphate-buffered saline (PDS)-inje cted retinas contained 61,165 +/- 4,932 (n = 10; P < 0.001 versus control r etinas) 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 nu mbers after GDNF treatment was confirmed by cell counts: obtained from froz en sections. CONCLUSIONS. GDNF exerts both histologic and functional neuroprotective eff ects on rod photoreceptors in the rd/rd mouse. Thus rescue was demonstrated in an animal model of inherited retinal degeneration in which the gene def ect was located within the rods themselves, similar to most forms of human retinitis pigmentosa. GDNF represents a candidate neurotrophic factor for p alliating some forms of hereditary human blindness.