Ординатура / Офтальмология / Английские материалы / Ocular Neuroprotection_Levin, Polo _2003

Labeling of Mu¨ller cells using antibodies directed against glial fibrillary acidic protein (GFAP), cellular retinaldehyde binding protein, and glutamine synthetase

Glutamate receptor GluR-2 immunohistochemical labeling Outer nuclear layer thickness and cell counts

Outer segment length

Quantification of apoptosis using the TUNEL technique Full-field and multi-focal ERG

Scotopic and photopic ERG

In the context of experimental RD, it has been only in recent years that studies have been conducted to investigate new approaches for either reducing the severity of retinopathic changes or improving retinal recovery following reattachment. Such experimental or neuroprotective therapies aimed at treating retinal changes in the context of RD are not as well defined as those strategies developed in the context of experimental models of light-induced and inherited photoreceptor degeneration [53]. Retinal detachments and photoreceptor degenerative diseases share a number of similar features, including time-dependent alterations in Mu¨ller cells (reactive gliosis and hypertrophy), photoreceptor cells (particularly synaptic changes), and ultimately apoptosis as the mechanism of photoreceptor cell death [54]. A number of the same survival factors (ciliary neurotrophic factor, brain-derived neurotrophic factor, pigment epithelium-de- rived factor, glial-derived neurotrophic factor, basic fibroblast growth factor, etc.) that enhance photoreceptor survival and function in the context of experimental models of photoreceptor degeneration are likely to have a similar effect in experimental RD.

Recent work has shown that brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) can mitigate the progression of a number of pathological retinal changes associated with experimental retinal detachments in the cat [55,56]. Lewis and colleagues showed that BDNF enhanced the organization and increased the length of outer segments and significantly reduced the proliferative changes of Mu¨ller cells while the retina was detached for 7 or 28 days. However, BDNF failed to reduce the overall photoreceptor cell death in this model. In a separate study, intravitreal GDNF was shown to increase the mean outer segment lengths in the detached retina when compared with control detachments [56].

A potentially important difference between models of photoreceptor degenerative diseases and experimental RD in the context of retinal neuroprotection may be the role of supplemental oxygen. In a pair of recently published studies, cat retinas were detached for three days, during which some animals were housed under hyperoxic conditions (70% ambient oxygen) and remaining animals were housed under normoxic conditions (21% ambient oxygen) [13,57]. Oxygen sup-

plementation was shown to promote the survival of photoreceptor cells, enhance the organizational structures of their outer segments, reduce Mu¨ller cell proliferation and hypertrophy, and normalize various aspects of the glutamate signaling system. These studies elegantly illustrate the importance of oxygen supplementation in decelerating a number of photoreceptor and retinal degenerative processes in RD. More recently, work in a ground squirrel model demonstrated that hyperoxia also rescued cone photoreceptors in this cone-dominant species, suggesting that survival of cones with hyperoxia is not necessarily secondary to survival of rods [58]. These studies on the effects of hyperoxia on photoreceptor survival provide a strong rationale for testing oxygen supplementation for enhancing visual outcome associated with the treatment of retinal detachments in the clinic.

Two factors play important roles in recovery of central vision following macula-off detachments: preoperative visual acuity and duration of the detachment [9]. In the absence of significant degeneration of the fovea, preoperative visual acuity is correlated with the height of the fovea from the RPE. Therefore, these clinical observations suggest that the ability to reduce the distance between the fovea and RPE and to speed retinal reattachment may improve visual outcome following reattachment. The RPE normally absorbs fluid in the subretinal-to- choroidal direction, and this RPE fluid “pump” function can be enhanced in vitro and in vivo by pharmacological means [1,59,60]. Thus, a pharmacological approach that stimulates the RPE pump could facilitate the removal of extraneous fluid in the subretinal space in RD and may provide a therapeutic approach for reducing the spread and height of the retinal separation. If sufficiently robust, pharmacological stimulation may reattach the retina without surgery; alternatively, it may be used as a surgical adjunct to minimize the spread of the detachment or facilitate the rate of reattachment. Carbonic anhydrase inhibitors acetazolamide and benzolamide have been shown to enhance subretinal fluid reabsorption in experimental subretinal blebs, presumably by activating the RPE fluid pump, and thereby facilitate retinal reattachment in rabbits [61,62]. However, acetazolamide is poorly tolerated, thus pointing to the need for alternative pharmacological means for stimulating the RPE pump.

The apical membrane of bovine RPE contains metabotropic P2Y2 receptors that respond to the natural ligands adenosine 5′-triphosphate (ATP) and uridine 5′-triphosphate (UTP) by activating membrane transport mechanisms and stimulating net apical-to-basolateral fluid absorption in vitro [63]. A synthetic P2Y2 receptor agonist INS37217, when delivered subretinally or intravitreally, has recently been shown to significantly enhance subretinal fluid reabsorption and retinal reattachment following experimental RD in rabbit [64] and rat [33]. Recent work in a mouse model of experimental RD also showed that INS37217 significantly enhanced the recovery rate of retinal function (as determined using standard ERG techniques) following retinal reattachment [78]. In the clinic, a pharmacological agent such as INS37217 that limits the spread of retinal detachments

and enhances retinal reattachment may provide a novel strategy for improving visual outcome following surgery.

V.MODELS OF RHEGMATOGENOUS, SEROUS, AND TRACTION RETINAL DETACHMENT

Machemer, Aaberg, and Norton developed an experimental model of rhegmatogenous retinal detachment in the owl monkey [8,29,35]. They defined the conditions that are necessary to produce and sustain long-standing rhegmatogenous RD, and concluded that alterations of the vitreous structure and creation of a relatively large retinal hole are required. Their basic technique is described in Figure 1B. They compared the histological effects of experimental verses naturally occurring retinal detachments in the owl monkey and found many similar features, including cystoid degeneration of the outer plexiform layer, degeneration of the outer and inner nuclear layers, and appearance of flat and multi-nucle- ated RPE cells [8]. Their model produced cystoid spaces and edema in the inner retina that developed and enlarged with time, and subsequently reabsorbed and disappeared following surgical reattachment of the retina [28]. These cystoid spaces were much larger and prominent than those reported from the experimental models of non-rhegmatogenous RD described by other investigators and do not appear to be artifacts of histological processing. It is unclear if these findings are species dependent, a result of surgical manipulation, or caused by the large retinal hole, but the observations of cystoid spaces and retinal edema are clinically relevant because they are found in long-standing human retinal detachments.

Pederson and colleagues published a series of papers in 1982 to 1986 that examined, among other things, some of the technical differences used in various approaches for creating rhegmatogenous versus non-rhegmatogenous RD [27, 34,65–67]. They were able to produce long term retinal detachments in rhesus monkeys by inducing a large bullous detachment (1 mL of 20% autologous serum in Ringer’s solution injected into the subretinal space), creating a large 2–3 mm retinal hole with a hooked tip of a 25-G needle, and following up with a subtotal vitrectomy. Without the vitrectomy, retinal detachments tended to spontaneously reattach [27]. In their model of rhegmatogenous RD, they found a transient and marked decrease in intraocular pressure and an increase in the rate of fluorescein disappearance from the vitreous. Based on these and other findings, they concluded that there is a posterior-directed flow of fluid through the retinal hole and that the RPE fluid pump function is increased.

Many models of traction RD have been developed using different methodologies [2,17,68–71]. A reproducible model of traction RD in the cat was created by first inducing a serous retinal detachment using the rose bengal method (see next paragraph), and then injecting dermal fibroblasts into the vitreous [68]. Trac-

tion RD was produced within the first 2 weeks after fibroblast injection, with characteristics of vitreoretinal strands and epiretinal proliferation. Retinal degeneration was observed in this model. The causes of the retinal degeneration may be attributed to multiple origins, including the associated photodynamic treatment for inducing the serous detachment, vascular thrombosis, and the prolonged detachment itself. Experimental traction RD was also observed following injection of autologous fibroblasts into the vitreous cavity of rabbits, and induction of perforating ocular injury in rabbits, pigs, and monkeys [69–71].

Serous retinal detachment is difficult to model. A reproducible model for serous RD utilizes intravenous administration of the dye rose bengal, which immediately photosensitizes the choroid and RPE and can be photochemically activated in the eye using a xenon photocoagulator filtered to a central wavelength of approximately 550 nm [72]. Adjusting the irradiance, duration of light exposure, and the dose of the rose bengal can control the peak and size of the resultant serous detachment. In the cat, Wilson and colleagues showed that serous retinal detachments as small as a focal retinal bleb (lasting 1 h) to a massive bullous detachment comprising the entire retina (lasting 4 months) were induced with this model. Considerable ischemic degeneration of the detached retina was observed in the region of the photothrombosis at 3 days following photodynamic injury, but the retina outside this region appeared relatively undamaged. For detachments that lasted for at least 7 days, there was a complete loss of photoreceptor outer segments, and for detachments that lasted at least 14 days, the neural retina was thin and gliotic with loss of the outer layers. Significant occlusion of blood vessels in the retina was also observed after 14 days of detachment. The need to photosensitize the choroid and induce significant photoactivated damage to the retina, RPE, and choroid indicate major disparities between the model and clinical serous RD. Experimental serous RD has also been created following occlusion of choroidal circulation with microsphere embolization and in experimental malignant hypertension [73–76]. To my knowledge, no systematic studies of experimental serous, traction, or rhegmatogenous retinal detachments have been conducted in the context of preventing retinal degeneration.

VI. CONCLUSION

Many experimental models of retinal detachment have been developed in the past few decades, and a number of them have been used to carefully define and understand various aspects of retinal alteration, remodeling, and degeneration. Quantitative and semiquantitative descriptions of retinal changes in experimental retinal detachment are important because they provide the investigator with measurable parameters to evaluate neuroprotective and other vision-salvaging strategies. There remains a significant medical need to enhance visual outcomes fol-

macula-off detachments are more frequently seen in the clinic and because loss of central visual acuity and color distortion are common following successful macular reattachment surgery, a better understanding of the cellular and electrophysiological effects of experimentally detached macula is needed. In Burton’s study, only 2% of patients operated on within 5 days of macular detachment were able to achieve postoperative visual acuity of 20/20 [9]. This 2% figure is illuminating: it tells us that in macula-off detachments it is indeed possible to restore visual acuity back to normal. The researcher is therefore motivated to find ways of utilizing experimental models of retinal detachment to develop new therapies that enable the capacity of foveal cones to recover fully. However, the remaining figure of 98% is daunting—it is a measure of the challenges that lay ahead.

ACKNOWLEDGMENT

I would like to thank Drs. Steve Fisher and Sheldon Miller for their valuable input and feedback on this chapter.

REFERENCES

1.Marmor MF. Control of subretinal fluid: experimental and clinical studies. Eye 1990; 4:340–344.

2.Martini B. Proliferative vitreo-retinal disorders: experimental models in vivo and in vitro. Acta Ophthalmol Suppl 1992; 201:1–63.

3.Fisher SK, Stone J, Rex TS, Linberg KA, Lewis GP. Experimental retinal detachment: a paradigm for understanding the effects of induced photoreceptor degeneration. Prog Brain Res 2001; 131:679–698.

4.Roberts SR. Detachment of the retina in animals. J Am Vet Med Ass 1959; 135: 423–435.

5.MacMillan AD. Acquired retinal folds in the cat. J Am Vet Med Assoc 1976; 168: 1015–1020.

6.Blair NP, Dodge JT, Schmidt GM. Rhegmatogenous retinal detachment in Labrador retrievers. I. Development of retinal tears and detachment. Arch Ophthalmol 1985; 103:842–847.

7.Blair NP, Dodge JT, Schmidt GM. Rhegmatogenous retinal detachment in Labrador retrievers. II. Proliferative vitreoretinopathy. Arch Ophthalmol 1985; 103:848–854.

8.Aaberg TM, Machemer R. Correlation of naturally occurring detachments with long-term retinal detachment in the owl monkey. Am J Ophthalmol 1970; 69:640– 650.

9.Burton TC. Recovery of visual acuity after retinal detachment involving the macula. Trans Am Ophthalmol Soc 1982; 80:475–497.

10.Anand R, Tasman WS. Nonrhegmatogenous retinal detachment. In: Glaser BM, ed. Retina. Vol. 3. St. Louis: Mosby, 1994:2463–2488.

11.Hay A, Lander MB. Types of pathogenetic mechanisms of retinal detachment. In: Glaser BM, ed. Retina. Vol. 3. St. Louis: Mosby, 1994:1971–1977.

12.Winkler B. The intermediary metabolism of the retina: biochemical and functional aspects. In: Anderson RE, ed. Biochemistry of the Eye. San Francisco: American Academy of Ophthalmology 1983:227–242.

13.Mervin K, Valter K, Maslim J, Lewis G, Fisher S, Stone J. Limiting photoreceptor death and deconstruction during experimental retinal detachment: the value of oxygen supplementation. Am J Ophthalmol 1999; 128:155–164.

14.Linsenmeier RA, Braun RD. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J Gen Physiol 1992; 99:177–197.

15.Wilkinson CP, Rice TA. Results of retinal reattachment surgery. In: Craven L, ed. Michels Retinal Detachment. St. Louis: Mosby, 1997:935–972.

16.The repair of rhegmatogenous retinal detachments. American Academy of Ophthalmology. Ophthalmology 1990; 97:1562–1572.

17.Ryan SJ. Traction retinal detachment. XLIX Edward Jackson Memorial Lecture. Am J Ophthalmol 1993; 115:1–20.

18.Marmor MF, Yao XY. Conditions necessary for the formation of serous detachment. Experimental evidence from the cat. Arch Ophthalmol 1994; 112:830–838.

19.Marmor MF, Yao XY. The metabolic dependency of retinal adhesion in rabbit and primate. Arch Ophthalmol 1995; 113:232–238.

20.Negi A, Kawano S, Marmor MF. Effects of intraocular pressure and other factors on subretinal fluid resorption. Invest Ophthalmol Vis Sci 1987; 28:2099–2102.

21.Anderson DH, Stern WH, Fisher SK, Erickson PA, Borgula GA. The onset of pigment epithelial proliferation after retinal detachment. Invest Ophthalmol Vis Sci 1981; 21:10–16.

22.Berglin L, Algvere PV, Seregard S. Photoreceptor decay over time and apoptosis in experimental retinal detachment. Graefes Arch Clin Exp Ophthalmol 1997; 235: 306–312.

23.Marmor MF, Abdul-Rahim AS, Cohen DS. The effect of metabolic inhibitors on retinal adhesion and subretinal fluid resorption. Invest Ophthalmol Vis Sci 1980; 19:893–903.

24.LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci USA 1992; 89:11249– 11253.

25.Flannery JG, Zolotukhin S, Vaquero MI, LaVail MM, Muzyczka N, Hauswirth WW. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94:6916–6921.

26.Machemer R. Macular translocation. Am J Ophthalmol 1998; 125:698–700.

27.Pederson JE, Cantrill HL, Cameron JD. Experimental retinal detachment. II. Role of the vitreous. Arch Ophthalmol 1982; 100:1155–1159.

28.Guerin CJ, Anderson DH, Fariss RN, Fisher SK. Retinal reattachment of the primate macula. Photoreceptor recovery after short-term detachment. Invest Ophthalmol Vis Sci 1989; 30:1708–1725.

29.Machemer R, Norton EW. Experimental retinal detachment and reattachment: I. Methods, clinical picture and histology. Bibl Ophthalmol 1969; 79:80–90.

30.Anderson DH, Stern WH, Fisher SK, Erickson PA, Borgula GA. Retinal detachment in the cat: the pigment epithelial-photoreceptor interface. Invest Ophthalmol Vis Sci 1983; 24:906–926.

31.Anderson DH, Guerin CJ, Erickson PA, Stern WH, Fisher SK. Morphological recovery in the reattached retina. Invest Ophthalmol Vis Sci 1986; 27:168–183.

32.Linberg KA, Lewis GP, Charteris DG, Fisher SK. Experimental detachment in a cone dominant retina. Invest Ophthalmol Vis Sci 1999; 40:S951.

33.Maminishkis A, Jalickee S, Blaug SA, Rymer J, Yerxa BR, Peterson WM, Miller SS. The P2Y2 receptor agonist INS37217 stimulates RPE fluids transport in vitro and retinal reattachment in rat. Invest Ophthalmol Vis Sci 2002; 43:3555–3566.

34.Pederson JE, MacLellan HM. Experimental retinal detachment. I. Effect of subretinal fluid composition on reabsorption rate and intraocular pressure. Arch Ophthalmol 1982; 100:1150–1154.

35.Machemer R, Norton EW. Experimental retinal detachment in the owl monkey. I. Methods of production and clinical picture. Am J Ophthalmol 1968; 66:388–396.

36.Marmor MF, Porteus M, Negi A, Immel J. Validation of a model of non-rhegmatog- enous retinal detachment. Curr Eye Res 1984; 3:515–518.

37.Wilkinson CP, Rice TA. Vitreoretinal precursors of retinal detachment. In: Craven L, ed. Micels Retinal Detachment. St. Louis: Mosby, 1997.

38.Hamasaki DI. An anatomical and electrophysiological study of the retina of the owl monkey, Aotes trivirgatus. J Comp Neurol 1967; 130:163–174.

39.Johnson LV, Hageman GS, Blanks JC. Interphotoreceptor matrix domains ensheath vertebrate cone photoreceptor cells. Invest Ophthalmol Vis Sci 1986; 27:129– 135.

40.Fisher SK, Steinberg RH. Origin and organization of pigment epithelial apical projections to cones in cat retina. J Comp Neurol 1982; 206:131–145.

41.Fariss RN, Molday RS, Fisher SK, Matsumoto B. Evidence from normal and degenerating photoreceptors that two outer segment integral membrane proteins have separate transport pathways. J Comp Neurol 1997; 387:148–156.

42.Linberg KA, Lewis GP, Shaaw C, Rex TS, Fisher SK. Distribution of S- and M- cones in normal and experimentally detached cat retina. J Comp Neurol 2001; 430: 343–356.

43.Nork TM, Millecchia LL, Strickland BD, Linberg JV, Chao GM. Selective loss of blue cones and rods in human retinal detachment. Arch Ophthalmol 1995; 113: 1066–1073.

44.Cook B, Lewis GP, Fisher SK, Adler R. Apoptotic photoreceptor degeneration in experimental retinal detachment. Invest Ophthalmol Vis Sci 1995; 36:990–996.

45.Chang CJ, Lai WW, Edward DP, Tso MO. Apoptotic photoreceptor cell death after traumatic retinal detachment in humans. Arch Ophthalmol 1995; 113:880–886.

46.Yamamoto S, Hayashi M, Takeuchi S. Cone electroretinograms in response to color stimuli after successful retinal detachment surgery. Jpn J Ophthalmol 1998; 42:314– 317.

47.Hayashi M, Yamamoto S. Changes of cone electroretinograms to colour flash stimuli after successful retinal detachment surgery. Br J Ophthalmol 2001; 85:410–413.

48.Sasoh M, Yoshida S, Kuze M, Uji Y. The multifocal electroretinogram in retinal detachment. Doc Ophthalmol 1997; 94:239–252.

49.Kamei S. [The recovery of the local ERG recorded from reattached retina after retinal detachment]. Nippon Ganka Gakkai Zasshi 1992; 96:776–783.

50.Mori T, Kamei S, Sugawara T, Tazawa Y. [Changes in retinal electrical response due to different size of experimental retinal detachment]. Nippon Ganka Gakkai Zasshi 1991; 95:1248–1251.

51.Imai K, Loewenstein A, de Juan E, Jr. Translocation of the retina for management of subfoveal choroidal neovascularization I: experimental studies in the rabbit eye. Am J Ophthalmol 1998; 125:627–634.

52.Kim SD, Nao-i N, Maruiwa F, Sawada A. Electrical responses from locally detached retina and its recovery after reattachment. Ophthalmologica 1996; 210:195–199.

53.Luthert PJ, Chong NH. Photoreceptor rescue. Eye 1998; 12:591–596.

54.Milam AH, Li ZY, Fariss RN. Histopathology of the human retina in retinitis pigmentosa. Prog Retin Eye Res 1998; 17:175–205.

55.Lewis GP, Linberg KA, Geller SF, Guerin CJ, Fisher SK. Effects of the neurotrophin brain-derived neurotrophic factor in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 1999; 40:1530–1544.

56.Lewis GP, Fisher SK. Glial cell-line derived neurotrophic factor (GDNF): retinal distribution and rescue effects on photoreceptors following experimental retinal detachment. Invest Ophthalmol Vis Sci 1998; 39:S572.

57.Lewis G, Mervin K, Valter K, et al. Limiting the proliferation and reactivity of retinal Muller cells during experimental retinal detachment: the value of oxygen supplementation. Am J Ophthalmol 1999; 128:165–172.

58.Sakai T, Lewis GP, Linberg KA, Fisher SK. The ability of hyperoxia to limit the effect of experimental detachment in cone-dominant retina. Invest Ophthalmol Vis Sci 2001; 42:3264–3273.

59.Hughes BA, Gallemore RP, Miller SS. Transport mechanisms in the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ, eds. The Retinal Pigment Epithelium. New York: Oxford University Press, 1998:103–134.

60.Peterson WM, Quong JN, Miller SS. Mechanisms of fluid transport in retinal pigment epithelium. The Third Great Basin Visual Science Symposium on Retinal Research 1998; III:34–42.

61.Marmor MF, Maack T. Enhancement of retinal adhesion and subretinal fluid resorption by acetazolamide. Invest Ophthalmol Vis Sci 1982; 23:121–124.

62.Wolfensberger TJ, Chiang RK, Takeuchi A, Marmor MF. Inhibition of membranebound carbonic anhydrase enhances subretinal fluid absorption and retinal adhesiveness. Graefes Arch Clin Exp Ophthalmol 2000; 238:76–80.

63.Peterson WM, Meggyesy C, Yu K, Miller SS. Extracellular ATP activates calcium signaling, ion, and fluid transport in retinal pigment epithelium. J Neurosci 1997; 17:2324–2337.

64.Meyer CH, Hotta K, Peterson WM, Toth CA, Jaffe GJ. Effect of INS37217, a P2Y2 receptor agonist, on experimental retinal detachment and electroretinogram in adult rabbits. Invest Ophthalmol Vis Sci 2002; 43:3567–3574.

65.Cantrill HL, Pederson JE. Experimental retinal detachment. III. Vitreous fluorophotometry. Arch Ophthalmol 1982; 100:1810–1813.

66.Pederson JE, Cantrill HL. Experimental retinal detachment. V. Fluid movement through the retinal hole. Arch Ophthalmol 1984; 102:136–139.

67.Kroll AJ, Machemer R. Experimental retinal detachment and reattachment in the rhesus monkey. Electron microscopic comparison of rods and cones. Am J Ophthalmol 1969; 68:58-77.

68.Wilson CA, Khawly JA, Hatchell DL, Machemer R. Experimental traction retinal detachment in the cat. Graefes Arch Clin Exp Ophthalmol 1991; 229:568–573.

69.Fastenberg DM, Diddie KR, Sorgente N, Ryan SJ. A comparison of different cellular inocula in an experimental model of massive periretinal proliferation. Am J Ophthalmol 1982; 93:559–564.

70.Cleary PE, Minckler DS, Ryan SJ. Ultrastructure of traction retinal detachment in rhesus monkey eyes after a posterior penetrating ocular injury. Am J Ophthalmol 1980; 90:829–845.

71.Gregor Z, Ryan SJ. Combined posterior contusion and penetrating injury in the pig eye. II. Histological features. Br J Ophthalmol 1982; 66:799–804.

72.Wilson CA, Royster AJ, Tiedeman JS, Hatchell DL. Exudative retinal detachment after photodynamic injury. Arch Ophthalmol 1991; 109:125–134.

73.Collier RH. Experimental embolic ischemia of the choroid. Arch Ophthalmol 1967; 77:683–692.

74.Gaudric A, Sterkers M, Coscas G. Retinal detachment after choroidal ischemia. Am J Ophthalmol 1987; 104:364–372.

75.Stern WH, Ernest JT. Microsphere occlusion of the choriocapillaris in rhesus monkeys. Am J Ophthalmol 1974; 78:438–448.

76.Kishi S, Tso MO, Hayreh SS. Fundus lesions in malignant hypertension. I. A pathologic study of experimental hypertensive choroidopathy. Arch Ophthalmol 1985; 103:1189-1197.

77.Jacobs GH, Calderone JB, Jakai T, Lewis GP, Fisher SK. An animal model for studying cone function in retinal detachment. Doc Ophthalmol 2002; 104:119–132.

78.Nour M, Alvarez K, Quiambao A, Peterson WM, Al-Ubaidi MR, Naasm MI. Effects of P2Y2 receptor agonist (INS37217) on recovery of retinal morphology and function following subretinal injections in mice: potential use in gene therapy delivery. Invest Ophthalmol Vis Sci 2002; 43: abstract #4610.