Photopic ERG negative response from amacrine cell signaling in RCS rat retinal degeneration

PURPOSE: The authors investigated photopic electroretinographic changes during degeneration in the Royal College of Surgeons (RCS) and transgenic P23H rhodopsin rat models, including the cellular origins of a large corneal-negative component that persists in the RCS rat. METHODS: Photopic and scotopic electroretinograms (ERGs) were recorded from dystrophic RCS (RCS-p(+)/Lav) rats (4-18 weeks old) and transgenic rhodopsin Pro23His line 1 (P23H) rats (4-30 weeks old). Age-matched congenic (RCS-rdy(+)p(+)/Lav) and Sprague-Dawley rats were used as controls. N-methyl-DL-aspartic acid (NMA), dopamine, and gamma-aminobutyric acid (GABA) were injected intravitreally, and optic nerve sectioning (ONS) was performed to suppress or remove inner retinal neuron activity. Retinal morphology for cone cell counts and immunohistochemistry for quantification of Kir4.1 channels were performed at various stages of degeneration. RESULTS: As degeneration progressed, the photopic ERG of RCS dystrophic rats was distinctly different from that of P23H rats, primarily because of the growth of a corneal-negative response (RCS-NPR) after the b-wave in RCS rats. This response had a peak time similar to the photopic negative response (PhNR) in controls but with a more gradual recovery phase, and it was not affected by ONS. The PhNR in P23H rats declined linearly with the b-wave. NMA and GABA eliminated the RCS-NPR and uncovered a larger b-wave in RCS rats at late stages of degeneration, but NMA had little effect on the ERG in P23H rats. The NMA-sensitive negative response in RCS rats declined with age more slowly than did the NMA-isolated b-wave. The density of Kir4.1 channels at the endfeet of Müller cells and in the proximal retina increased significantly between 6 to 10 weeks and 14 weeks of age in the RCS rat retina but not in the P23H rat retina. CONCLUSIONS: The photopic ERG of the dystrophic RCS rat retina becomes increasingly electronegative because of an aberrant negative response, originating from amacrine cell activity, which declines more slowly than the b-wave with degeneration. The absence of this response in the P23H rat indicates that the inner retinal cone pathway pathology is different in the two models. A relative increase in Kir4.1 channels on Müller cells of RCS retina may contribute to the enhanced negative ERG response in the RCS rat.     

睫状神经营养因子及其受体在正常及变性视网膜中表达水平与分布的变化

目的 观察正常Sprague-Dawley（SD）和遗传性视网膜变性Royal College of Surgeons (RCS)大鼠视网膜发育过程中睫状神经营养因子(CNTF)及其受体(CNTFR)的表达水平与分布特点。 方法 新生至成年(12个月龄) SD和RCS大鼠视网膜石蜡切片，免疫组织化学染色显示睫状神经营养因子及其受体表达水平和分布变化。 结果 出生后0～7 d,SD大鼠神经视网膜全层染色呈阳性，随着周龄增加，节细胞染色明显增强，而其他细胞染色减弱，至28 d时节细胞染色达高峰，并持续至老年；RCS大鼠视网膜CNTF免疫组织化学染色结果与SD大鼠基本相同。出生后0～3 d, SD大鼠神经视网膜全层CNTFR的表达呈弱阳性，节细胞染色稍深，在将来要发育成外节处可见断续阳性染色；随着周龄增加，光感受器外节处阳性染色逐渐增强，14～28 d染色达到高峰；56 d时外节染色减弱，而节细胞染色却明显增强，直至老年。3～14 d RCS大鼠视网膜CNTFR染色基本与同龄SD大鼠一致，但21 d起外节染色明显减弱，28 d时外节染色基本呈阴性，但节细胞仍呈强阳性，一直持续到老年。 结论 CNTF的表达在正常和变性大鼠间无明显差异；CNTFR主要在节细胞和光感受器外节处高水平表达，正常和变性RCS大鼠间存在显著差异，为利用CNTF治疗视网膜变性提供了实验证据。 (中华眼底病杂志, 2006, 22: 120-123)     

RCS大鼠视网膜内核层变性的超微结构研究

目的　证实RCS大鼠视网膜内核层存在神经原变性。方法　利用光学显微镜和透射电子显微镜观察出生后第 18、2 0、2 8、3 5、42、45、5 6、60、70和 10 0d的RCS大鼠视网膜和正常SD大鼠视网膜组织结构的变化。并用TUNEL方法证实视网膜神经细胞存在凋亡。结果　和正常SD大鼠视网膜比较 ,RCS大鼠 18～ 2 0d开始视网膜变性 ,光感受器细胞死亡 ,内核层细胞也有不同程度的变性。RCS大鼠在出生后 2 5d ,视网膜外核层细胞核TUNEL呈阳性 ,出生后 3 5～ 45d呈强阳性 ,视网膜内核层细胞核TUNEL标记呈阳性。结论　RCS大鼠视网膜内核层细胞存在神经原变性 ,视网膜内核层细胞死亡存在凋亡这一方式。跨神经原变性很可能是这些细胞变性的机制。RCS大鼠视网膜外核层细胞存在神经原变性 ,其死亡以凋亡为主     

Light treatment enhances photoreceptor survival in dystrophic retinas of Royal College of Surgeons rats.

PURPOSE: To determine whether treatment with bright light elicits a protective response that enhances photoreceptor survival in Royal College of Surgeons (RCS) rats with inherited retinal degeneration. METHODS: RCS rats were illuminated for 10 to 12 hours with 130 foot-candles (fc) of white or green light. Untreated littermates that were kept under low cyclic light levels were used as control subjects. Photoreceptor survival was determined by quantitative analysis of photoreceptor nuclei and ultrastructural assessment of cellular organization. Basic fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF) gene expression were determined at the mRNA and protein levels. RESULTS: Treatments of RCS rats with a single dose of bright light on postnatal day 23 (P23) greatly enhanced photoreceptor survival. Ultrasturctural analysis revealed intact inner segments in light-treated retinas, whereas in untreated retinas only remnants of inner segments were observed. By P42, numerous viable nuclei were counted in the posterior retina of light-treated rats, whereas most of the remaining nuclei in untreated RCS rat retinas were highly pyknotic. At 2.5 days after treatment with a single dose of bright light, bFGF gene expression was significantly higher than in untreated RCS rat retinas. By P42, bFGF protein levels were still significantly higher in the treated retinas. CONCLUSIONS: Exogenous bFGF has been shown to promote photoreceptor survival in the RCS rat retina. Thus, the increased bFGF expression that was measured in the light-treated RCS rat retinas may be a protective response to light stress, which supports the observed rescue of photoreceptors in light-treated RCS rat retinas.     

Low expression of rhodopsin kinase in pineal gland in Royal College of Surgeons rat

The Royal College of Surgeons (RCS) rat has been extensively characterized as a model for inherited retinal dystrophy such as retinitis pigmentosa. We have found that significantly low levels of expression of rhodopsin kinase (RK) and alphaA-crystallin may be involved in the pathogenesis of retinal degeneration in the RCS rat (Invest Ophthalmol Vis Sci. 1999,40:2788-2794). In the present study, we examined the expression of photoreceptor specific proteins in the pineal gland (PG) including rhodopsin kinase (RK), arrestin and recoverin, which are known to be commonly present in both photoreceptor and PG, in order to elucidate the pathological relationship between retina and PG during retinal degeneration. Among these proteins, RK expression was significantly decreased with advancing age (3-5 weeks old) in RCS rat. However, in contrast, arrestin expression in RCS PG was comparable with control PG and no expressions of recoverin and other G-protein coupled receptor kinases (GRKs 2, 5 and 6) were detected in RCS PG during 3-5 weeks of age. By administration of nilvadipine, an effective Ca2+ antagonist that was shown to preserve RCS retinal degeneration, RK expression was significantly enhanced.     

Activation of mitochondrial calpain and release of apoptosis-inducing factor from mitochondria in RCS rat retinal degeneration

The present study was performed to investigate changes of cytosolic and mitochondrial calpain activities, and effects of intravitreously injected calpain inhibitor on photoreceptor apoptosis in Royal College of Surgeon’s (RCS) rats. Time courses of activities for both cytosolic and mitochondrial calpains and amount of calpastatin in RCS rat retina were analyzed by subcellular fractionation, calpain assay and western blotting. Calpain assay was colorimetrically performed using Suc-LLVY-Glo as substrate. Effects of intravitreously injected calpain inhibitor (ALLN and PD150606) on RCS rat retinal degeneration were analyzed by TUNEL staining. Effects of mitochondrial calpain activity on activation and translocation of apoptosis-inducing factor (AIF) were analyzed by western blotting. Mitochondrial calpain started to be significantly activated at postnatal (p) 28 days in RCS rat retina, whereas cytosolic μ-calpain was activated at p 35 days, although specific activity of mitochondrial calpain was 13% compared to cytosolic μ-calpain. Intravitreously injected ALLN and PD150606 effectively inhibited photoreceptor apoptosis only when injected at p 25 days, but did not inhibit photoreceptor apoptosis when injected at p 32 days. Parts of AIF were truncated/activated by mitochondrial calpains and translocated to the nucleus. These results suggest that 1), calpain presents not only in the cytosolic fraction but also in the mitochondrial fraction in RCS rat retina; 2), mitochondrial calpain is activated earlier than cytosolic calpain during retinal degeneration in RCS rats; 3), photoreceptor apoptosis may be regulated by not only calpain systems but also other mechanisms; 4), mitochondrial calpain may activate AIF to induce apoptosis; and 5), calpain inhibitors may be partially effective to inhibit photoreceptor apoptosis in RCS rats. The present study provides new insights into the molecular basis for photoreceptor apoptosis in RCS rats and the future possibility of new pharmaceutical treatments for retinitis pigmentosa.     

A comparative study of distribution of 70 kD stress protein in the retina between the normal and retinal dystrophic rat]

The immunolocalization of 70 kD stress protein (SP70) was investigated in the retinal tissues of normal Sprague-Dawley (SD) rat and that of the Royal College of Surgeons (RCS) rat with inherited retinal dystrophy. From postnatal day 2 to 15, SP70 was present in the maturing retinal tissues of both rat strains. In the RCS rat retina of postnatal day 22, at the onset of retinal degeneration, SP70 was expressed in the retinal pigment epithelium (RPE). At postnatal day 40, immunostaining for SP70 was considerably reduced in the degenerating RCS retina. In the RCS retina at postnatal day 90, immunostaining for SP70 was completely lost except for the ganglion cells and the inner plexiform layers. These results suggested that, at the onset of retinal degeneration, the RCS retina may have a state of metabolic stress, which induced SP70 expression in the RPE. At the end stage of retinal degeneration, the immunostaining for SP70 was lost, suggesting the lack of production of SP70 in the degenerated retinal tissue.     

Chronic intravitreous infusion of ciliary neurotrophic factor modulates electrical retinal stimulation thresholds in the RCS rat

PURPOSE: To determine whether the sustained intravitreous delivery of CNTF modulates cortical response thresholds to electrical retinal stimulation in the RCS rat model of retinal degeneration. METHODS: Animals were assigned to four groups: untreated, nonsurgical control and infusion groups of 10 ng/d CNTF, 1 ng/d CNTF, and PBS vehicle control. Thresholds for electrically evoked cortical potentials (EECPs) were recorded in response to transcorneal electrical stimulation of the retina at p30 and again at p60, after a three-week infusion. RESULTS: As the retina degenerated over time, EECP thresholds in response to electrical retinal stimulation increased. Eyes treated with 10 ng/d CNTF demonstrated significantly greater retinal sensitivity to electrical stimulation when compared with all other groups. In addition, eyes treated with 1 ng/d CNTF demonstrated significantly greater retinal sensitivity than both PBS-treated and untreated control groups. CONCLUSIONS: Retinal sensitivity to electrical stimulation was preserved in animals treated with chronic intravitreous infusion of CNTF. These data suggest that CNTF-mediated retinal neuroprotection may be a novel therapy that can lower stimulus thresholds in patients about to undergo retinal prosthesis implantation. Furthermore, it may maintain the long-term efficacy of these devices in patients.     

Cataracts in the Royal College of Surgeons rat: evidence for initiation by lipid peroxidation products

The Royal College of Surgeons (RCS) rat has been extensively studied as a model system for inherited retinal degeneration. As in a number of human retinal degenerative diseases, posterior subcapsular cataracts (PSC) are associated with the retinal changes. It has been hypothesized recently that such cataracts may be initiated by toxic products generated by the peroxidation of polyunsaturated lipid components from degenerating photoreceptor outer segments. In the present study, the possibility that such a mechanism might be responsible for cataract initiation in the RCS rat has been investigated. The degeneration of the rod outer segments (ROS) occurs rapidly in these animals, beginning a few weeks after birth. Due to the failure of the retinal pigmented epithelium to phagocytize normally, ROS degeneration is accompanied by an accumulation of debris in the eye. During the brief period of maximal debris accumulation there is a marked increase in lipid peroxidation products in the vitreous. Cataract formation is correlated temporally with these events, becoming evident immediately following the time during which peroxidation products are present in the vitreous. In addition, the primary damage detected in the RCS lenses is an increase in the passive permeability of the lens membranes. Similar lens damage has been found in studies in which normal rat lenses were exposed to degenerating ROS in vitro. These findings are consistent with the hypothesis that cataracts in the RCS rat may be initiated by toxic lipid peroxidation products.     

Retinal sensitivity measured by the pupillary light reflex in RCS and albino rats

The effects of retinal degeneration on the sensitivity of the retina were studied in the Royal College of Surgeons (RCS) rat by measuring the light reflex of the pupil in response to ganzfeld (full field) flashes. Light reflex thresholds were measured for animals from 32 to 683 days of age, and an age-related decrease in sensitivity of 5.2 log units (maximum) was measured. In contrast, thresholds for non-dystrophic albino controls increased only slightly during a comparable period. RCS rat thresholds increased more for short wavelength light than for long wavelength light. The end result was an altered action spectrum of the light reflex which largely, but not exclusively, reflected cone function. Even in cases of advanced degeneration the light reflex thresholds we measured showed significant input from rods. Pupillary dark adaptation measured following ganzfeld bleaches (10%) with test stimuli of two different wavelengths revealed two mechanisms; a photopic mechanism (λ_max = 520) determined thresholds early in dark adaptation, but later a scotopic mechanism (λ_max = 500) participated in the light reflex.     

Is there a humoral autoimmune response to retinal antigens in the RCS rat?

The naturally occurring humoral immune response of Campbell and Hunter strains of Royal College of Surgeons (RCS) rat to bovine retinal S-antigen and bovine rod outer segments was tested by a sensitive ELISA (enzyme linked immunosorbent assay) in animals up to the age of 9 weeks. Controls of Piebald Virol Glaxo, Wistar and DA rats were also employed. The ELISA results indicate that rats of all strains had a response to both antigens. The magnitude of the response in any particular strain varied with the age of the animal and the antigen and serum dilution employed in the assay. Considerable variation in response was observed among animals of the same strain at any one particular age. Immunoblot analysis of the strongest ELISA positive sera detected S-antigen and other autoantigenic proteins in both RCS and Wistar rats. The data suggest that the antibody response observed may have little significance to the retinal degeneration observed with RCS rats.     

Transplantation of iris pigment epithelium into the choroid slows down the degeneration of photoreceptors in the RCS rat

Background:Trophic factors [e.g. basic fibroblast growth factor (bFGF)] released by transplanted retinal pigment epithelial (RPE) cells are able to slow down the hereditary degeneration of the retina in the Royal College of Surgeons rat in sites distant from the site of transplantation where rod outer segment (ROS) phagocytic activity is not reconstituted by the transplants. Methods:To investigate whether iris pigmented epithelial (IPE) cells are also able to generate this rescue by trophic factors, we transplanted IPE cells from Long-Evans rats into the choroid and subretinal space of 17 young RCS rats. The eyes were enucleated after 6 months and prepared for light microscopy. Six age-matched RCS rats served as controls. Light microscope sections from the whole choroid, healthy choriocapillaris, transplanted cells and the maximum thickness of the choroid, and outer nuclear layer parameters were analyzed by computer-assisted morphometry. Results:In transplanted animals photoreceptor cells were rescued from degeneration although the majority of the transplanted IPE cells were located in the choroid. In the non-transplanted group photoreceptors were absent. Conclusions:Transplantation of IPE cells slows down degeneration of the photoreceptors in the RCS rat. This photoreceptor-sparing effect by the IPE cells was observed even when the transplants were predominantly located within the choroid. The beneficial effect observed may be related to trophic factors possibly secreted by the transplanted IPE cells. Received: 31 January 2000 Revised: 31 May 2000 Accepted: 19 June 2000     

Developmental study of chondroitin-6-sulphate in normal and dystrophic rat retina

The RCS rat is a widely studied model of human retinal dystrophies including retinitis pigmentosa. Chondroitin-6-sulphate (C6S) in the interphotoreceptor matrix was localised immunocytochemically in both the normal congenic and dystrophic strains of the RCS rat up to 65 days postnatally. From postnatal days 5 to 15 the distribution of C6S in both strains was similar, being localised in the interstices of developing inner and outer segments and adjacent to the RPE surface. In the normal rats, the distribution of C6S did not change with age. In the RCS rats, however, at postnatal days 20 to 35 staining was observed as a dense band at the junction of inner and outer segments and no staining was observed adjacent to the surface of the RPE. At postnatal day 45 onwards there was a decrease and a complete absence of C6S staining in these rats. This change in the pattern of staining correlated with the morphological observation of the progressive degeneration of photoreceptor cells suggesting that C6S may be important in photoreceptor degeneration in the RCS rat.Correspondence to: L.N. WalkerThis study was partially supported by the Australian Retinitis Pigmentosa Association and Appealathon Foundation of Western Australia, NH & MRC, ORIA and OPSM Research Foundations     

Preservation of retinal morphology and functions in royal college surgeons rat by nilvadipine, a Ca(2+) antagonist

PURPOSE: The Royal College of Surgeons (RCS) rat is the most extensively studied animal model for understanding the molecular pathology in inherited retinal degeneration, such as retinitis pigmentosa (RP). The purpose of the present study was to evaluate the pharmacologic effects of several Ca(2+) antagonists on the retinal degeneration of RCS rats. METHODS: Several Ca(2+) antagonists, diltiazem, nicardipine, nilvadipine, and nifedipine, were intraperitoneally administered and retinal morphology and functions analyzed. RESULTS: Among the Ca(2+) antagonists, only intraperitoneally administered nilvadipine preserved retinal morphology and electroretinogram responses in RCS rats during the initial stage of retinal degeneration. Studies using immunohistochemistry, RT-PCR, and Western blot analysis revealed significant enhancement of rhodopsin kinase and alphaA-crystallin expression and suppression of caspase 1 and 2 expression in the retina of nilvadipine-treated rats. CONCLUSIONS: These data suggest that nilvadipine is beneficial for the preservation of photoreceptor cells in RCS rats and can be used to treat some patients with RP.     

Optokinetic nystagmus thresholds of dark-adapted RCS rats

The thresholds of dark adapted RCS rats and controls were estimated from optokinetic responses to blue stimuli, and compared to thresholds derived from b-wave stimulus/response functions. The rats were tested at ages 25, 30 and 35 days, a period during which the RCS degeneration is evolving and normal retinal development is proceeding. At all ages the OKN thresholds of control rats were lower than those of the RCS rats, but only by age 30 days did b-wave thresholds discriminate RCS from controls. As the RCS disease progressed b-wave thresholds increased, but OKN thresholds did not change significantly. The discrepancy between the OKN and b-wave results may be due largely to the smaller OKN stimulus field, which probably stimulates mainly the posterior retina where the RCS degeneration is most advanced.     

Numbers of cortical vitreous cells and onset of cataracts in Royal College of surgeons rats

Royal College of Surgeons (RCS) rats have hereditary retinal degeneration with associated posterior subcapsular opacities. A link between light, retinal degeneration, and cataracts may consist in peroxidation of polyunsaturated fatty acids of rod outer segment lipids to yield water-soluble toxic aldehydes that can traverse the vitreous and react with bow cells and posterior lens fibers. In an immune reaction to the retinal degeneration, macrophages multiply in the retina and in the cortex of the vitreous. In dystrophics, the cortical vitreous separates readily from attachments to retina, ciliary body and lens, and from the vitreous gel. This web-like structure was stained and spread on a counting chamber. Cells were counted at 15-130 postnatal days in pink- and black-eyed RCS dystrophics and in congenic controls to correlate numbers of cells, temporal and geographic patterns of retinal degeneration, and onset of opacities. Rats were reared in cyclic light (10-40 lux inside the cage) and fed a natural ingredient diet (NIH-07). Cortical vitreous cells increased markedly in pink- and black-eyed dystrophics at 50-53 days when slit-lamp detectable opacities occurred in both. The increase was 4.6-fold in pink- and 2.3-fold in black-eyed rats compared with controls. At 50-53 days, the dystrophy affected all quadrants of the retina severely in pink-eyed RCS but only the inferior periphery in black-eyed RCS. Consequently, severe degeneration in one quadrant may suffice to initiate an opacity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporal and spatial characteristics of cone degeneration in RCS rats

Purpose  

The temporal and spatial characteristics of cone degeneration in the Royal College of Surgeons (RCS) rat were studied to provide information for treatment strategies of retinitis pigmentosa.     

The Effect of Intravitreal <Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="SmallCaps">dl</Emphasis>-Aspartic Acid on the Electroretinogram in Royal College of Surgeons Rats

Purpose

To investigate how the third-order neuronal response contributes to shaping the electroretinogram (ERG) in the Royal College of Surgeons (RCS) rat.

Methods

Full-field ERGs were recorded from dystrophic RCS rats (n = 30) at 4, 6, 8, 10, 12, or 14 weeks of age in response to different stimulus intensities (maximum intensity, 0.84?log?cd-s/m²). N-methyl-dl-aspartic acid (NMDA, 5?mM) was injected into the vitreous cavity of the right eyes to eliminate the third-order neuronal response. The left eyes received the vehicle and served as controls. The third-order neuronal response was isolated by digitally subtracting waveforms of the NMDA-injected eyes from those of the control eyes.

Results

The ERG a- and b-waves deteriorated with the age of the rat. The third-order neuronal response was preserved to a greater degree than the b-wave despite progression of photoreceptor degeneration. Intravitreal injection of NMDA attenuated the a-wave and enhanced the b-wave across the stimulus range from low to middle intensities. This tendency became more pronounced with advancing rat age. In aged dystrophic RCS rats this phenomenon was seen even at maximum intensity. The difference between NMDA-injected and vehicle-injected eyes was larger for the threshold than for the maximum amplitude at each examined time point (P < 0.001). Intravitreal injection of NMDA decreased implicit times of the a- and b-waves after the rats reached 8 weeks of age (P < 0.005 for the a-wave).

Conclusion

With advancing photoreceptor degeneration, the third-order neuronal response made a greater contribution to shaping the a- and b-waves in dystrophic RCS rats.?Jpn J Ophthalmol 2007;51:165–174 © Japanese Ophthalmological Society 2007

     

An in vivo Study of Basic Fibroblast Growth Factor on Activation and Proliferation of Retinal Progenitor Cells in RCS Rat

Purpose: To investigate the effect of intravitreal injection of basic fibroblast growth factor(bFGF)on activation and proliferation of endogenous retinal progenitor cells in the Royal College of Surgeons(RCS)rat.Methods: Twenty-four rats were studied after the 30th postnatal day(≥ 30).Eighteen RCS-p+/LAV rats were divided into 3 groups: bFGF-treated,vehicle-treated and untreated groups randomly,and 6 RCS-ray+p+/Lav respectively rats were used as normal controls.6 μl of bFGF(5 μg/10 μl)or vehicle was injected into the vitreous on day 31,33 and 35 after birth(P31,P33,P35)in the bFGF group and vehicle group respectively,and no injections were administered in the untreated and control groups.All the rats were euthanized,and their eyes were enucleated,hemisected and fixed at 50 days after birth for immunohistochemistry and measurement of outer nuclear layer thickness.Results:Nestin and Chx10 were positive in all retinal layers,intravitreal injection of bFGF in retina-dystrophic RCS(RCS-p+/Lav)rats induced intense labeling for the retinal progenitor cell markers Chx10 and Nestin,which were highly colocalized.Fluorescence intensity for both labels was somewhat less in the control rats,and much less in the vehicle-injected rats as well as in the untreated RCS rats.The outer nuclear layer(ONL)was significantly thicker in bFGF group than that in vehicle-treated or untreated group(P<0.01),but thinner than that of the control group(P<0.01).No significant difference was observed in the ONL thickness between the vehicle group and untreated group(P>0.05).Conclusion:bFGF may contribute to the activation of retinal progenitor cells in RCS rats,thus counteract degeneration by promoting the proliferation of the progenitor cells.     

Intraretinal oxygen levels before and after photoreceptor loss in the RCS rat

PURPOSE: To measure the intraretinal oxygen environment at different stages in the Royal College of Surgeons (RCS) rat model of retinal degeneration to determine whether changes in oxygen level are an important aspect of the disease. METHODS: Oxygen-sensitive microelectrodes were used to measure oxygen tension as a function of depth through the retina of anesthetized, mechanically ventilated RCS rats at ages ranging from postnatal day (P)20 to P104. The oxygen profiles were correlated with histologic observations of the cellular changes within the dystrophic retinas and compared with those in RCS-rdy(+) control animals and published values in normal mature rats. RESULTS: Although the youngest rats studied exhibited some differences in intraretinal oxygen distribution compared with mature animals, the distribution in dystrophic RCS rats at P20 was not significantly different from that in age-matched control subjects. However, the intraretinal oxygen distribution in dystrophic RCS rats was clearly affected after approximately P30, reflecting a loss of photoreceptor oxygen consumption consistent with histologic observations. In contrast, oxygen uptake by the inner retina was still evident long after the loss of photoreceptors was essentially complete. CONCLUSIONS: There was no significant tissue hypoxia during photoreceptor degeneration in the dystrophic RCS rat. The changes in intraretinal oxygen distribution are consistent with the loss of outer retinal oxygen uptake but the preservation of inner retinal oxygen metabolism.