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Purpose: To examine the protective effect of a number of survival factors on degenerating photoreceptors in mutant mice with naturally occurring inherited retinal degenerations, including retinal degeneration (rd/rd), retinal degeneration slow (rds/rds), nervous (nr/nr), and Purkinje cell degeneration (pcd/pcd), in three different forms of mutant rhodopsin transgenic mice and in light damage in albino mice., Methods: Various survival factors were injected intravitreally into one eye of mice at or soon after the beginning of photoreceptor degeneration, with the opposite eye serving as the control, and the eyes were examined histologically at later ages. The survival factors included brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, ciliary neurotrophic factor (CNTF), Axokine (a mutein of CNTF), leukemia inhibitory factor, basic fibroblast growth factor, and nerve growth factor and insulin-like growth factor II, either alone or in various combinations., Results: Photoreceptor degeneration was slowed in rd/rd and nr/nr mutant mice and in Q344ter mutant rhodopsin mice by certain forms of CNTF; the degeneration in Q344ter mice was slowed by Axokine and by leukemia inhibitory factor; and the degeneration in a few nr/nr mice was slowed by BDNF. The other agents were ineffective in these mice, and none of the agents were effective in the other mutants and other mutant rhodopsin transgenic mice. However, light damage experiments that compared agent effectiveness in albino mice versus rats suggested a significant delivery problem with the very small mouse eye, thereby making the interpretation of negative findings equivocal in mutant mice. Basic fibroblast growth factor failed to protect the mouse retina from the damaging effects of constant light, whereas it showed a strong protective effect in the rat, indicating an important species difference., Conclusions: The slowing of degeneration in the rd/rd and Q344ter mutant mice demonstrated that intraocularly injected survival factors can protect photoreceptors from degenerating in animal models with the same or similar genetic defects as those in human inherited retinal degenerations.

Purpose: To investigate whether and how survival-promoting agents rescue photoreceptor cell function and morphology from constant light damage, the authors recorded electroretinographic (ERG) responses and examined light micrographs of retinas in those rats given intravitreal injection of midkine (MK) and basic fibroblast growth factor (bFGF) before constant exposure., Methods: Albino Sprague-Dawley rats were injected with MK, bFGF, or phosphate-buffered saline (PBS) 2 days before the onset of 1 week of constant light. ERG responses were recorded using white flash stimuli with the intensity range of 4 log units, followed by histologic examinations of retinas, including quantitative assessment of the outer nuclear layer thickness as an index of photoreceptor cell loss., Results: ERG responses were barely detectable in uninjected eyes after 1 week of constant light. On the other hand, distinct responses were recordable in eyes injected intravitreally with MK and bFGF, and the degree of ERG rescue in terms of the amplitude of b-wave was approximately 40% to 60% compared with normal eyes. Intravitreally injected PBS showed slight, but noticeable, preservation of ERG responses as well. Histologic examination revealed that MK and bFGF protected photoreceptors from light damage. A good correlation was found between anatomic rescue of photoreceptors as assessed by outer nuclear layer thickness and the functional rescue as defined by the magnitude of ERG responses., Conclusions: Functional and anatomic rescue of photoreceptors in albino rats from constant light damage is achieved by prior intravitreal injection of MK and bFGF.

Ultrastructural changes in the distribution of free ribosomes in photoreceptor inner segments in relation to photoreceptor degeneration in Purkinje cell degeneration (pcd) were studied in mutant mice reared under cyclic light and sacrificed at 30 and 120 postnatal days. On postnatal day 30, some photoreceptors appeared to be normal whereas others had degenerated to varying degrees with numerous spherules in the extracellular space surrounding degenerating inner segments. By postnatal day 120, retinal degeneration had progressed with a marked loss of photoreceptors. The distribution of free ribosomes in the mutant inner segments was random, clustered, or uniform. This was distinct from normal control retinas in which random distribution predominated. Markedly degenerated inner segments contained sparse ribosomes which coalesced in small aggregates. These changes in ribosome distribution seemed to be associated with the extent of photoreceptor degeneration. The significance of these changes in ribosome distribution, in particular clustered distribution, is discussed together with our previous findings.

Purpose: To evaluate the protective effects of midkine (MK), the product of a retinoic acid-responsive gene, on constant light-induced retinal degeneration in albino Sprague-Dawley rats., Methods: Midkine, basic fibroblast growth factor (bFGF), MK plus heparin, or buffer controls were injected intravitreally 2 days before constant light exposure. After 7 days of continuous light exposure, the eyes were perfused with fixative, bisected along the vertical meridian, embedded in paraffin, and sectioned. The degree of retinal light damage was assessed for paraffin-embedded sections by cytologic analysis, by measuring the thickness of the outer nuclear layer (ONL), and by counting the number of macrophages., Results: After 1 week of constant light exposure, uninjected controls and those injected with phosphate-buffered saline (PBS) lost most of the photoreceptor inner and outer segments, and the thickness of the ONL was decreased. Eyes that were injected with MK or bFGF demonstrated a significant rescue in the photoreceptor layer with a two- to threefold increase in the ONL thickness. The number of macrophages in eyes injected with MK was significantly suppressed compared with controls. Those injected with bFGF had a 1.5-fold increase in number compared with controls., Conclusions: Midkine has shown strong survival-promoting activity in constant light-induced retinal degeneration, and thus has a high degree of neurotrophic activity in vivo.