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Proc Natl Acad Sci U S A. Dec 1, 1992; 89(23): 11249–11253.

Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light.


Recent demonstrations of survival-promoting activity by neurotrophic agents in diverse neuronal systems have raised the possibility of pharmacological therapy for inherited and degenerative disorders of the central nervous system. We have shown previously that, in the retina, basic fibroblast growth factor delays photoreceptor degeneration in Royal College of Surgeons rats with inherited retinal dystrophy and that the growth factor reduces or prevents the rapid photoreceptor degeneration produced by constant light in the rat. This light-damage model now provides an efficient way to assess quantitatively the survival-promoting activity in vivo of a number of growth factors and other molecules. We report here that photoreceptors can be significantly protected from the damaging effects of light by intravitreal injection of eight different growth factors, cytokines, and neurotrophins that typically act through several distinct receptor families. In addition to basic fibroblast growth factor, those factors providing a high degree of photoreceptor rescue include brain-derived neurotrophic factor, ciliary neurotrophic factor, interleukin 1 beta, and acidic fibroblast growth factor; those with less activity include neurotrophin 3, insulin-like growth factor II, and tumor necrosis factor alpha; those showing little or no protective effect are nerve growth factor, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor I, heparin, and laminin. Although we used at least one relatively high concentration of each agent (the highest available), it is still possible that other concentrations or factor combinations might be more protective. Injecting heparin along with acidic fibroblast growth factor or basic fibroblast growth factor further enhanced the degree of photoreceptor survival and also suppressed the increased incidence of macrophages produced by either factor, especially basic fibroblast growth factor. These results now provide the impetus for determining the normal function in the retina, mechanism(s) of rescue, and therapeutic potential in human eye diseases for each agent.

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  • Adler R, Landa KB, Manthorpe M, Varon S. Cholinergic neuronotrophic factors: intraocular distribution of trophic activity for ciliary neurons. Science. 1979 Jun 29;204(4400):1434–1436. [PubMed]
  • Johnson JE, Barde YA, Schwab M, Thoenen H. Brain-derived neurotrophic factor supports the survival of cultured rat retinal ganglion cells. J Neurosci. 1986 Oct;6(10):3031–3038. [PubMed]
  • Kalcheim C, Barde YA, Thoenen H, Le Douarin NM. In vivo effect of brain-derived neurotrophic factor on the survival of developing dorsal root ganglion cells. EMBO J. 1987 Oct;6(10):2871–2873. [PMC free article] [PubMed]
  • Sievers J, Hausmann B, Unsicker K, Berry M. Fibroblast growth factors promote the survival of adult rat retinal ganglion cells after transection of the optic nerve. Neurosci Lett. 1987 May 6;76(2):157–162. [PubMed]
  • Carmignoto G, Maffei L, Candeo P, Canella R, Comelli C. Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci. 1989 Apr;9(4):1263–1272. [PubMed]
  • Otto D, Frotscher M, Unsicker K. Basic fibroblast growth factor and nerve growth factor administered in gel foam rescue medial septal neurons after fimbria fornix transection. J Neurosci Res. 1989 Jan;22(1):83–91. [PubMed]
  • Rodriguez-Tébar A, Jeffrey PL, Thoenen H, Barde YA. The survival of chick retinal ganglion cells in response to brain-derived neurotrophic factor depends on their embryonic age. Dev Biol. 1989 Dec;136(2):296–303. [PubMed]
  • Arakawa Y, Sendtner M, Thoenen H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci. 1990 Nov;10(11):3507–3515. [PubMed]
  • Hohn A, Leibrock J, Bailey K, Barde YA. Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature. 1990 Mar 22;344(6264):339–341. [PubMed]
  • Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM, Yancopoulos GD. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990 Mar 23;247(4949 Pt 1):1446–1451. [PubMed]
  • Sendtner M, Kreutzberg GW, Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature. 1990 May 31;345(6274):440–441. [PubMed]
  • Tuszynski MH, U HS, Amaral DG, Gage FH. Nerve growth factor infusion in the primate brain reduces lesion-induced cholinergic neuronal degeneration. J Neurosci. 1990 Nov;10(11):3604–3614. [PubMed]
  • Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature. 1991 Mar 21;350(6315):230–232. [PubMed]
  • Ip NY, Li YP, van de Stadt I, Panayotatos N, Alderson RF, Lindsay RM. Ciliary neurotrophic factor enhances neuronal survival in embryonic rat hippocampal cultures. J Neurosci. 1991 Oct;11(10):3124–3134. [PubMed]
  • Oppenheim RW, Prevette D, Yin QW, Collins F, MacDonald J. Control of embryonic motoneuron survival in vivo by ciliary neurotrophic factor. Science. 1991 Mar 29;251(5001):1616–1618. [PubMed]
  • Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature. 1990 Sep 6;347(6288):83–86. [PubMed]
  • LaVail MM, Faktorovich EG, Hepler JM, Pearson KL, Yasumura D, Matthes MT, Steinberg RH. Basic fibroblast growth factor protects photoreceptors from light-induced degeneration in albino rats. Ann N Y Acad Sci. 1991;638:341–347. [PubMed]
  • Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat. J Neurosci. 1992 Sep;12(9):3554–3567. [PubMed]
  • Edgar D, Timpl R, Thoenen H. The heparin-binding domain of laminin is responsible for its effects on neurite outgrowth and neuronal survival. EMBO J. 1984 Jul;3(7):1463–1468. [PMC free article] [PubMed]
  • Lipton SA, Wagner JA, Madison RD, D'Amore PA. Acidic fibroblast growth factor enhances regeneration of processes by postnatal mammalian retinal ganglion cells in culture. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2388–2392. [PMC free article] [PubMed]
  • Burke JM. Stimulation of DNA synthesis in human and bovine RPE by peptide growth factors: the response to TNF-alpha and EGF is dependent upon culture density. Curr Eye Res. 1989 Dec;8(12):1279–1286. [PubMed]
  • Campochiaro PA, Sugg R, Grotendorst G, Hjelmeland LM. Retinal pigment epithelial cells produce PDGF-like proteins and secrete them into their media. Exp Eye Res. 1989 Aug;49(2):217–227. [PubMed]
  • Leschey KH, Hackett SF, Singer JH, Campochiaro PA. Growth factor responsiveness of human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1990 May;31(5):839–846. [PubMed]
  • Waldbillig RJ, Pfeffer BA, Schoen TJ, Adler AA, Shen-Orr Z, Scavo L, LeRoith D, Chader GJ. Evidence for an insulin-like growth factor autocrine-paracrine system in the retinal photoreceptor-pigment epithelial cell complex. J Neurochem. 1991 Nov;57(5):1522–1533. [PubMed]
  • LaVail MM, Gorrin GM, Repaci MA, Thomas LA, Ginsberg HM. Genetic regulation of light damage to photoreceptors. Invest Ophthalmol Vis Sci. 1987 Jul;28(7):1043–1048. [PubMed]
  • Martiney JA, Litwak M, Berman JW, Arezzo JC, Brosnan CF. Pathophysiologic effect of interleukin-1b in the rabbit retina. Am J Pathol. 1990 Dec;137(6):1411–1423. [PMC free article] [PubMed]
  • O'Steen WK, Karcioglu ZA. Phagocytosis in the light-damaged albino rat eye: light and electron microscopic study. Am J Anat. 1974 Apr;139(4):503–517. [PubMed]
  • Dionne CA, Jaye M, Schlessinger J. Structural diversity and binding of FGF receptors. Ann N Y Acad Sci. 1991;638:161–166. [PubMed]
  • Meakin SO, Shooter EM. The nerve growth factor family of receptors. Trends Neurosci. 1992 Sep;15(9):323–331. [PubMed]
  • Davis S, Aldrich TH, Valenzuela DM, Wong VV, Furth ME, Squinto SP, Yancopoulos GD. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. [PubMed]
  • Hicks D, Courtois Y. Acidic fibroblast growth factor stimulates opsin levels in retinal photoreceptor cells in vitro. FEBS Lett. 1988 Jul 18;234(2):475–479. [PubMed]
  • Lehwalder D, Jeffrey PL, Unsicker K. Survival of purified embryonic chick retinal ganglion cells in the presence of neurotrophic factors. J Neurosci Res. 1989 Oct;24(2):329–337. [PubMed]
  • Kuwabara T, Gorn RA. Retinal damage by visible light. An electron microscopic study. Arch Ophthalmol. 1968 Jan;79(1):69–78. [PubMed]
  • Grignolo A, Orzalesi N, Castellazzo R, Vittone P. Retinal damage by visible light in albino rats. An electron microscope study. Ophthalmologica. 1969;157(1):43–59. [PubMed]
  • Spina MB, Squinto SP, Miller J, Lindsay RM, Hyman C. Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system. J Neurochem. 1992 Jul;59(1):99–106. [PubMed]
  • Barbe MF, Tytell M, Gower DJ, Welch WJ. Hyperthermia protects against light damage in the rat retina. Science. 1988 Sep 30;241(4874):1817–1820. [PubMed]
  • Edward DP, Lam TT, Shahinfar S, Li J, Tso MO. Amelioration of light-induced retinal degeneration by a calcium overload blocker. Flunarizine. Arch Ophthalmol. 1991 Apr;109(4):554–562. [PubMed]
  • Steinberg RH. Research update: report from a workshop on cell biology of retinal detachment. Exp Eye Res. 1986 Nov;43(5):695–706. [PubMed]
  • Schweigerer L, Malerstein B, Neufeld G, Gospodarowicz D. Basic fibroblast growth factor is synthesized in cultured retinal pigment epithelial cells. Biochem Biophys Res Commun. 1987 Mar 30;143(3):934–940. [PubMed]
  • Sternfeld MD, Robertson JE, Shipley GD, Tsai J, Rosenbaum JT. Cultured human retinal pigment epithelial cells express basic fibroblast growth factor and its receptor. Curr Eye Res. 1989 Oct;8(10):1029–1037. [PubMed]
  • Plouët J, Mascarelli F, Loret MD, Faure JP, Courtois Y. Regulation of eye derived growth factor binding to membranes by light, ATP or GTP in photoreceptor outer segments. EMBO J. 1988 Feb;7(2):373–376. [PMC free article] [PubMed]
  • Hageman GS, Kirchoff-Rempe MA, Lewis GP, Fisher SK, Anderson DH. Sequestration of basic fibroblast growth factor in the primate retinal interphotoreceptor matrix. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6706–6710. [PMC free article] [PubMed]
  • Hewitt AT, Lindsey JD, Carbott D, Adler R. Photoreceptor survival-promoting activity in interphotoreceptor matrix preparations: characterization and partial purification. Exp Eye Res. 1990 Jan;50(1):79–88. [PubMed]
  • Mascarelli F, Tassin J, Courtois Y. Effect of FGFs on adult bovine Muller cells: proliferation, binding and internalization. Growth Factors. 1991;4(2):81–95. [PubMed]
  • Roberge FG, Caspi RR, Nussenblatt RB. Glial retinal Müller cells produce IL-1 activity and have a dual effect on autoimmune T helper lymphocytes. Antigen presentation manifested after removal of suppressive activity. J Immunol. 1988 Apr 1;140(7):2193–2196. [PubMed]
  • Rappolee DA, Werb Z. Macrophage-derived growth factors. Curr Top Microbiol Immunol. 1992;181:87–140. [PubMed]

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