High resolution imaging of fluorescein patterns in RCS rat retinae and their direct correlation with histology

Zambarakji, Hadi; Keegan, David; Holmes, Toby; Halfyard, Anthony S; Villegas‐Pérez, María Paz; Charteris, David G.; Fitzke, F.W.; Greenwood, John; Lund, Raymond D.

doi:10.1016/j.exer.2005.06.006

Cited by 17 publications

(13 citation statements)

References 39 publications

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“…There is evidence that photoreceptor degeneration is closely related to vasculopathy in the diseased retina [8], [13], [14], [35]. We observed that RCS rats developed progressive capillary dropout and both intra- and sub-retinal neovascularization as they aged.…”

Section: Discussionmentioning

confidence: 66%

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Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

et al. 2014

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ObjectiveRoyal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats.MethodsFluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34+ cells and mobilization of CD34+/VEGF-R2+ cells as well as recruitment of CD34+ cells into the retina were examined after EPO treatment.ResultsRCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34+ cells along with effective mobilization of CD34+/VEGF-R2+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina.ConclusionsOur results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells.

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Section: Discussionmentioning

confidence: 66%

“…There is evidence that loss of photoreceptors in animal models of retinal degenerations has a profound effect on vascular development of the retina [8]. Recent studies indicate that the progressive loss of photoreceptors in RCS rats is accompanied by capillary dropout and growth of subretinal neovascularization [13], [14].…”

Section: Introductionmentioning

confidence: 99%

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

et al. 2014

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“…Because in this study we have observed proliferating microglial cells, it is possible that the increased numbers of microglial cells in both experimental models is due to microglial cell division, although it might be also in part due to macrophage migration from the blood or the subretinal space. In fact, breakdown of the blood-retinal barrier has been documented in these animal models (Zambarakji et al, 2006; Pinilla et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Early Events in Retinal Degeneration Caused by Rhodopsin Mutation or Pigment Epithelium Malfunction: Differences and Similarities

et al. 2017

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To study the course of photoreceptor cell death and macro and microglial reactivity in two rat models of retinal degeneration with different etiologies. Retinas from P23H-1 (rhodopsin mutation) and Royal College of Surgeon (RCS, pigment epithelium malfunction) rats and age-matched control animals (Sprague-Dawley and Pievald Viro Glaxo, respectively) were cross-sectioned at different postnatal ages (from P10 to P60) and rhodopsin, L/M- and S-opsin, ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acid protein (GFAP), and proliferating cell nuclear antigen (PCNA) proteins were immunodetected. Photoreceptor nuclei rows and microglial cells in the different retinal layers were quantified. Photoreceptor degeneration starts earlier and progresses quicker in P23H-1 than in RCS rats. In both models, microglial cell activation occurs simultaneously with the initiation of photoreceptor death while GFAP over-expression starts later. As degeneration progresses, the numbers of microglial cells increase in the retina, but decreasing in the inner retina and increasing in the outer retina, more markedly in RCS rats. Interestingly, and in contrast with healthy animals, microglial cells reach the outer nuclei and outer segment layers. The higher number of microglial cells in dystrophic retinas cannot be fully accounted by intraretinal migration and PCNA immunodetection revealed microglial proliferation in both models but more importantly in RCS rats. The etiology of retinal degeneration determines the initiation and pattern of photoreceptor cell death and simultaneously there is microglial activation and migration, while the macroglial response is delayed. The actions of microglial cells in the degeneration cannot be explained only in the basis of photoreceptor death because they participate more actively in the RCS model. Thus, the retinal degeneration caused by pigment epithelium malfunction is more inflammatory and would probably respond better to interventions by inhibiting microglial cells.

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“…Previous reports 8,12–15 have thoroughly documented the progressive photoreceptor degeneration in RCS rats by using anatomic methods. By 3 weeks of age, photoreceptor outer segments show evidence of disruption with the development of an apical debris zone.…”

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confidence: 99%

Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography

Ryals

Andrews

Datta

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeProspective treatments for age-related macular degeneration and inherited retinal degenerations are commonly evaluated in the Royal College of Surgeons (RCS) rat before translation into clinical application. Historically, retinal thickness obtained through postmortem anatomic assessments has been a key outcome measure; however, utility of this measurement is limited because it precludes the ability to perform longitudinal studies. To overcome this limitation, the present study was designed to provide a baseline longitudinal quantification of retinal thickness in the RCS rat by using spectral-domain optical coherence tomography (SD-OCT).MethodsHorizontal and vertical linear SD-OCT scans centered on the optic nerve were captured from Long-Evans control rats at P30, P60, P90 and from RCS rats between P17 and P90. Total retina (TR), outer nuclear layer+ (ONL+), inner nuclear layer (INL), and retinal pigment epithelium (RPE) thicknesses were quantified. Histologic sections of RCS retina obtained from P21 to P60 were compared to SD-OCT images.ResultsIn RCS rats, TR and ONL+ thickness decreased significantly as compared to Long-Evans controls. Changes in INL and RPE thickness were not significantly different between control and RCS retinas. From P30 to P90 a subretinal hyperreflective layer (HRL) was observed and quantified in RCS rats. After correlation with histology, the HRL was identified as disorganized outer segments and the location of accumulated debris.ConclusionsRetinal layer thickness can be quantified longitudinally throughout the course of retinal degeneration in the RCS rat by using SD-OCT. Thickness measurements obtained with SD-OCT were consistent with previous anatomic thickness assessments. This study provides baseline data for future longitudinal assessment of therapeutic agents in the RCS rat.

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High resolution imaging of fluorescein patterns in RCS rat retinae and their direct correlation with histology

Cited by 17 publications

References 39 publications

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

Early Events in Retinal Degeneration Caused by Rhodopsin Mutation or Pigment Epithelium Malfunction: Differences and Similarities

Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography

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