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Neurotrophin Family Members as Neuroprotectants in Retinal Degenerations

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Abstract

Background and Objectives

Inherited retinal degenerations (IRDs) are an untreatable cause of blindness due to photoreceptor apoptosis. Blocking apoptosis by exogenous neurotrophic factor administration is a promising therapeutic strategy in IRDs. The neurotrophin (NT) family are a group of peptide growth factors homologous to nerve growth factor that regulate the development, differentiation, survival, and function of neuronal cells. This mini-review summarizes the preclinical evidence for neuroprotection of photoreceptors by NTs and explores the molecular pathways responsible for this protective effect.

Methods

Studies published in the literature over the past 20 years that report on the effect of NTs on apoptotic photoreceptor death in IRDs and light-induced retinal degeneration, and the cellular pathways involved, are reviewed.

Results

Preclinical evidence suggests that exogenous NT administration may be protective against photoreceptor apoptosis. Each NT exerts a neuroprotective effect on photoreceptors that is specific depending upon the model of retinal degeneration and the delivery system. Signaling pathways and retinal cells mediating this effect are still uncertain. Alternatively, different NTs may protect or damage photoreceptors depending on the expression pattern of high- and low-affinity NT receptors on the retinal cells.

Conclusions

Although there is evidence that NTs may exert a protective effect, most likely indirectly on photoreceptor cell apoptotic degeneration in IRDs, the precise cellular and molecular mechanisms underlying this effect are still largely unknown. Better understanding of these mechanisms may greatly improve the rationale and efficacy of NT strategy for treatment of IRDs.

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References

  1. Chang GQ, Hao Y, Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron. 1993;11:595–605.

    CAS  PubMed  Google Scholar 

  2. Dryja TP, Berson EL. Retinitis pigmentosa and allied diseases. Implications of genetic heterogeneity. Invest Ophthalmol Vis Sci. 1995;36:1197–200.

    CAS  PubMed  Google Scholar 

  3. Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature. 1990;347:83–6.

    CAS  PubMed  Google Scholar 

  4. Hojo M, Abe T, Sugano E, Yoshioka Y, Saigo Y, Tomita H, et al. Photoreceptor protection by iris pigment epithelial transplantation transduced with AAV-mediated brain-derived neurotrophic factor gene. Invest Ophthalmol Vis Sci. 2004;45:3721–6.

    PubMed  Google Scholar 

  5. Kano T, Abe T, Tomita H, Sakata T, Ishiguro S, Tamai M. Protective effect against ischemia and light damage of iris pigment epithelial cells transfected with the BDNF gene. Invest Ophthalmol Vis Sci. 2002;43:3744–53.

    PubMed  Google Scholar 

  6. 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;89:11249–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. LaVail MM, Yasumura D, Matthes MT, Lau-Villacorta C, Unoki K, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci. 1998;39:592–602.

    CAS  PubMed  Google Scholar 

  8. Lawrence JM, Keegan DJ, Elizabeth MM, Coffey PJ, Rogers JH, Wilby MJ, et al. Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic royal college of surgeons rats. Invest Ophthalmol Vis Sci. 2004;45:267–74.

    PubMed  Google Scholar 

  9. Lambiase A, Aloe L. Nerve growth factor delays retinal degeneration in C3H mice. Graefes Arch Clin Exp Ophthalmol. 1996;234(Suppl 1):S96–100.

    CAS  PubMed  Google Scholar 

  10. Lenzi L, Coassin M, Lambiase A, Bonini S, Amendola T, Aloe L. Effect of exogenous administration of nerve growth factor in the retina of rats with inherited retinitis pigmentosa. Vis Res. 2005;45:1491–500.

    CAS  PubMed  Google Scholar 

  11. Okoye G, Zimmer J, Sung J, Gehlbach P, Deering T, Nambu H, et al. Increased expression of brain-derived neurotrophic factor preserves retinal function and slows cell death from rhodopsin mutation or oxidative damage. J Neurosci. 2003;23:4164–72.

    CAS  PubMed  Google Scholar 

  12. Levi-Montalcini R, Hamburger V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool. 1951;116:321–61.

    CAS  PubMed  Google Scholar 

  13. Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1982;1:549–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Ernfors P, Ibáñez CF, Ebendal T, Olson L, Persson H. Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain. Proc Natl Acad Sci U S A. 1990;87:5454–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Berkemeier LR, Winslow JW, Kaplan DR, Nikolics K, Goeddel DV, Rosenthal A. Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB. Neuron. 1991;7:857–66.

    CAS  PubMed  Google Scholar 

  16. Hallböök F. Evolution of the vertebrate neurotrophin and Trk receptor gene families. Curr Opin Neurobiol. 1999;9:616–21.

    PubMed  Google Scholar 

  17. Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294:1945–8.

    CAS  PubMed  Google Scholar 

  18. Srinivasan B, Roque CH, Hempstead BL, Al-Ubaidi MR, Roque RS. Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor. J Biol Chem. 2004;279:41839–45.

    CAS  PubMed  Google Scholar 

  19. McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL. New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor. Nature. 1991;354:411–4.

    CAS  PubMed  Google Scholar 

  20. Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science. 1991;252:554–8.

    CAS  PubMed  Google Scholar 

  21. Klein N, Nanduri V, Jing S, Lamballe F, Tapley P, Bryant S, et al. The trkB tyrosine kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 1991;66:395–403.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Lamballe F, Klein R, Barbacid M. trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell. 1991;66:967–79.

    CAS  PubMed  Google Scholar 

  23. Rodriguez-Tebar A, Dechnat G, Barde YA. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron. 1990;4:487–92.

    CAS  PubMed  Google Scholar 

  24. Ultsch MH, Wiesmann C, Simmons LC, Henrich J, Yang M, Reilly D, et al. Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC. J Mol Biol. 1999;290:149–59.

    CAS  PubMed  Google Scholar 

  25. Liepinsh E, Ilag LL, Otting G, Ibáñez CF. NMR structure of the death domain of the p75 neurotrophin receptor. EMBO J. 1997;16:4999–5005.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2003;72:609–42.

    CAS  PubMed  Google Scholar 

  27. Segal RA, Greenberg ME. Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci. 1996;19:463–89.

    CAS  PubMed  Google Scholar 

  28. Kalb R. The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci. 2005;28:5–11.

    CAS  PubMed  Google Scholar 

  29. Gille H, Sharrocks AD, Shaw PE. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature. 1992;358:414–7.

    CAS  PubMed  Google Scholar 

  30. Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995;80:199–211.

    CAS  PubMed  Google Scholar 

  31. Corbit KC, Foster DA, Rosner MR. Protein kinase Cdelta mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells. Mol Cell Biol. 1999;19:4209–18.

    PubMed Central  CAS  PubMed  Google Scholar 

  32. Brunet A, Datta SR, Greenberg ME. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001;11:297–305.

    CAS  PubMed  Google Scholar 

  33. Aloyz RS, Bamji SX, Pozniak CD, Toma JG, Atwal J, Kaplan DR, et al. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J Cell Biol. 1998;143:1691–703.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Casademunt E, Carter BD, Benzel I, Frade JM, Dechant G, Barde YA. The zinc finger protein NRIF interacts with the neurotrophin receptor p75(NTR) and participates in programmed cell death. EMBO J. 1999;18:6050–61.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Hirata H, Hibasami H, Yoshida T, Ogawa M, Matsumoto M, Morita A, et al. Nerve growth factor signaling of p75 induces differentiation and ceramide-mediated apoptosis in Schwann cells cultured from degenerating nerves. Glia. 2001;36:245–58.

    CAS  PubMed  Google Scholar 

  36. Roux PP, Bhakar AL, Kennedy TE, Barker PA. The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway. J Biol Chem. 2001;276:23097–104.

    CAS  PubMed  Google Scholar 

  37. Ishikawa Y, Ikeuchi T, Hatanaka H. Brain-derived neurotrophic factor accelerates nitric oxide donor-induced apoptosis of cultured cortical neurons. J Neurochem. 2000;75:494–502.

    CAS  PubMed  Google Scholar 

  38. Kim HJ, Hwang JJ, Behrens MM, Snider BJ, Choi DW, Koh JY. TrkB mediates BDNF-induced potentiation of neuronal necrosis in cortical culture. Neurobiol Dis. 2003;14:110–9.

    CAS  PubMed  Google Scholar 

  39. Mamidipudi V, Wooten MW. Dual role for p75(NTR) signaling in survival and cell death: can intracellular mediators provide an explanation? J Neurosci Res. 2002;68:373–84.

    CAS  PubMed  Google Scholar 

  40. Agarwal N, Agarwal R, Kumar DM, Ondricek A, Clark AF, Wordinger RJ, et al. Comparison of expression profile of neurotrophins and their receptors in primary and transformed rat retinal ganglion cells. Mol Vis. 2007;13:1311–8.

    CAS  PubMed  Google Scholar 

  41. Carmignoto G, Comelli MC, Candeo P, Cavicchioli L, Yan Q, Meriggi A, et al. Expression of NGF receptor and NGF receptor mRNA in the developing and adult rat retina. Exp Neurol. 1991;111:302–11.

    CAS  PubMed  Google Scholar 

  42. Di Polo A, Cheng L, Bray GM, Aguayo AJ. Colocalization of TrkB and brain-derived neurotrophic factor proteins in green-red–sensitive cone outer segments. Invest Ophthalmol Vis Sci. 2000;41:4014–21.

    PubMed  Google Scholar 

  43. Koide T, Takahashi JB, Hoshimaru M, Kojima M, Otsuka T, Asahi M, et al. Localization of trkB and low-affinity nerve growth factor receptor mRNA in the developing rat retina. Neurosci Lett. 1995;185:183–6.

    CAS  PubMed  Google Scholar 

  44. Perez MT, Caminos E. Expression of brain-derived neurotrophic factor and of its functional receptor in neonatal and adult rat retina. Neurosci Lett. 1995;183:96–9.

    CAS  PubMed  Google Scholar 

  45. Rickman DW, Brecha NC. Expression of the proto-oncogene, trk, receptors in the developing rat retina. Vis Neurosci. 1995;12:215–22.

    CAS  PubMed  Google Scholar 

  46. Suzuki A, Nomura S, Morii E, Fukuda Y, Kosaka J. Localization of mRNAs for trkB isoforms and p75 in rat retinal ganglion cells. J Neurosci Res. 1998;54:27–37.

    CAS  PubMed  Google Scholar 

  47. Takahashi JB, Hoshimaru M, Kikuchi H, Hatanaka M. Developmental expression of trkB and low-affinity NGF receptor in the rat retina. Neurosci Lett. 1993;151:174–7.

    CAS  PubMed  Google Scholar 

  48. Ugolini G, Cremisi F, Maffei L. TrkA, TrkB and p75 mRNA expression is developmentally regulated in the rat retina. Brain Res. 1995;704:121–4.

    CAS  PubMed  Google Scholar 

  49. Vecino E, Caminos E, Ugarte M, Martín-Zanca D, Osborne NN. Immunohistochemical distribution of neurotrophins and their receptors in the rat retina and the effects of ischemia and reperfusion. Gen Pharmacol. 1998;30:305–14.

    CAS  PubMed  Google Scholar 

  50. Zanellato A, Comelli MC, Dal Toso R, Carmignoto G. Developing rat retinal ganglion cells express the functional NGF receptor p140trkA. Dev Biol. 1993;15:105–13.

    Google Scholar 

  51. Cellerino A, Kohler K. Brain-derived neurotrophic factor/neurotrophin-4 receptor TrkB is localized on ganglion cells and dopaminergic amacrine cells in the vertebrate retina. J Comp Neurol. 1997;386:149–60.

    CAS  PubMed  Google Scholar 

  52. García M, Forster V, Hicks D, Vecino E. In vivo expression of neurotrophins and neurotrophin receptors is conserved in adult porcine retina in vitro. Invest Ophthalmol Vis Sci. 2003;44:4532–41.

    PubMed  Google Scholar 

  53. Nag TC, Wadhwa S. Neurotrophin receptors (Trk A, Trk B, and Trk C) in the developing and adult human retina. Brain Res Dev Brain Res. 1999;117:179–89.

    CAS  PubMed  Google Scholar 

  54. Cui Q, Tang LS, Hu B, So KF, Yip HK. Expression of trkA, trkB, and trkC in injured and regenerating retinal ganglion cells of adult rats. Invest Ophthalmol Vis Sci. 2002;43:1954–64.

    PubMed  Google Scholar 

  55. Cao GF, Liu Y, Yang W, Wan J, Yao J, Wan Y, et al. Rapamycin sensitive mTOR activation mediates nerve growth factor (NGF) induced cell migration and pro-survival effects against hydrogen peroxide in retinal pigment epithelial cells. Biochem Biophys Res Commun. 2011;414:499–505.

    CAS  PubMed  Google Scholar 

  56. Cellerino A, Pinzón-Duarte G, Carroll P, Kohler K. Brain-derived neurotrophic factor modulates the development of the dopaminergic network in the rodent retina. J Neurosci. 1998;18:3351–62.

    CAS  PubMed  Google Scholar 

  57. Wahlin KJ, Campochiaro PA, Zack DJ, Adler R. Neurotrophic factors cause activation of intracellular signaling pathways in Muller cells and other cells of the inner retina, but not photoreceptors. Invest Ophthalmol Vis Sci. 2000;4:927–36.

    Google Scholar 

  58. Wahlin KJ, Adler R, Zack DJ, Campochiaro PA. Neurotrophic signaling in normal and degenerating rodent retinas. Exp Eye Res. 2001;73:693–701.

    CAS  PubMed  Google Scholar 

  59. Hackett SF, Friedman Z, Freund J, Schoenfeld C, Curtis R, DiStefano PS, et al. A splice variant of trkB and brain-derived neurotrophic factor are co-expressed in retinal pigmented epithelial cells and promote differentiated characteristics. Brain Res. 1998;789:201–12.

    CAS  PubMed  Google Scholar 

  60. Rohrer B, Korenbrot JI, LaVail MM, Reichardt LF, Xu B. Role of neurotrophin receptor TrkB in the maturation of rod photoreceptors and establishment of synaptic transmission to the inner retina. J Neurosci. 1999;19:8919–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Rohrer B, Matthes MT, LaVail MM, Reichardt LF. Lack of p75 receptor does not protect photoreceptors from light- induced cell death. Exp Eye Res. 2003;76:125–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Oku H, Ikeda T, Honma Y, Sotozono C, Nishida K, Nakamura Y, et al. Gene expression of neurotrophins and their high-affinity Trk receptors in cultured human Müller cells. Ophthalmic Res. 2002;34:38–42.

    CAS  PubMed  Google Scholar 

  63. Harada T, Harada C, Nakayama N, Okuyama S, Yoshida K, Kohsaka S, et al. Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light- induced retinal degeneration. Neuron. 2000;26:533–41.

    CAS  PubMed  Google Scholar 

  64. Das I, Sparrow JR, Lin MI, Shih E, Mikawa T, Hempstead BL. Trk C signaling is required for retinal progenitor cell proliferation. J Neurosci. 2000;20:2887–95.

    CAS  PubMed  Google Scholar 

  65. Yip HK, So KF. Localization of p75 neurotrophin receptor in the retina of the adult SD rat: an immunocytochemical study at light and electron microscopic levels. Glia. 1998;24:187–97.

    PubMed  Google Scholar 

  66. Nakamura K, Harada C, Okumura A, Namekata K, Mitamura Y, Yoshida K, et al. Effect of p75NTR on the regulation of photoreceptor apoptosis in the rd mouse. Mol Vis. 2005;11:1229–35.

    CAS  PubMed  Google Scholar 

  67. Ikeda K, Tanihara H, Tatsuno T, Noguchi H, Nakayama C. Brain-derived neurotrophic factor shows a protective effect and improves recovery of the ERG b-wave response in light-damage. J Neurochem. 2003;87:290–6.

    CAS  PubMed  Google Scholar 

  68. LaVail MM, Nishikawa S, Duncan JL, Yang H, Matthes MT, Yasumura D, et al. Sustained delivery of NT-3 from lens fiber cells in transgenic mice reveals specificity of neuroprotection in retinal degenerations. J Comp Neurol. 2008;511:724–35.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Caffé R, Söderpalm AK, Holmqvist I, Van Veen T. Combination of CNTF and BDNF rescues rd photoreceptors but changes rod differentiation in the presence of RPE in retinal explants. Invest Ophthalmol Vis Sci. 2001;42:275–82.

    PubMed  Google Scholar 

  70. Bringmann A, Reichenbach A. Role of Muller cells in retinal degenerations. Front Biosci. 2001;6:E72–92.

    CAS  PubMed  Google Scholar 

  71. Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, et al. Microglia-Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J Neurosci. 2002;22:9228–36.

    CAS  PubMed  Google Scholar 

  72. Zack DJ. Neurotrophic rescue of photoreceptors: are Muller cells the mediators of survival? Neuron. 2000;26:285–6.

    CAS  PubMed  Google Scholar 

  73. Fontaine V, Kinkl N, Sahel J, Dreyfus H, Hicks D. Survival of purified rat photoreceptors in vitro is stimulated directly by fibroblast growth factor-2. J Neurosci. 1998;18:9662–72.

    CAS  PubMed  Google Scholar 

  74. Kinkl N, Sahel J, Hicks D. Alternate FGF2-ERK1/2 signaling pathways in retinal photoreceptor and glial cells in vitro. J Biol Chem. 2001;276:43871–8.

    CAS  PubMed  Google Scholar 

  75. Kinkl N, Hageman GS, Sahel JA, Hicks D. Fibroblast growth factor receptor (FGFR) and candidate signaling molecule distribution within rat and human retina. Mol Vis. 2002;8:149–60.

    PubMed  Google Scholar 

  76. Valter K, van Driel D, Bisti S, Stone J. FGFR1 expression and FGFR1-FGF-2 colocalisation in rat retina: sites of FGF-2 action on rat photoreceptors. Growth Factors. 2002;20:177–88.

    CAS  PubMed  Google Scholar 

  77. Asai N, Abe T, Saito T, Sato H, Ishiguro S, Nishida K. Temporal and spatial differences in expression of TrkB isoforms in rat retina during constant light exposure. Exp Eye Res. 2007;85:346–55.

    CAS  PubMed  Google Scholar 

  78. Wenzel A, Grimm C, Marti A, Kueng-Hitz N, Hafezi F, Niemeyer G, et al. c-fos Controls the private pathway of light-induced apoptosis of retinal photoreceptors. J Neurosci. 2000;20:81–8.

    CAS  PubMed  Google Scholar 

  79. Cachafeiro M, Bemelmans AP, Samardzija M, Afanasieva T, Pournaras JA, Grimm C, et al. Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability. Cell Death Dis. 2013;4:e781.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Campos X, Muñoz Y, Selman A, Yazigi R, Moyano L, Weinstein-Oppenheimer C, et al. Nerve growth factor and its high-affinity receptor trkA participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer. Gynecol Oncol. 2007;104:168–75.

    CAS  PubMed  Google Scholar 

  81. Julio-Pieper M, Lozada P, Tapia V, Vega M, Miranda C, Vantman D, et al. Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway. J Clin Endocrinol Metab. 2009;94:3065–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Romon R, Adriaenssens E, Lagadec C, Germain E, Hondermarck H, Le Bourhis X. Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Mol Cancer. 2010;9:157.

    PubMed Central  PubMed  Google Scholar 

  83. Nakamura K, Tan F, Li Z, Thiele CJ. NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1α. Mol Cell Neurosci. 2011;46:498–506.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Foote CS. Mechanisms of photosensitized oxidation. There are several different types of photosensitized oxidation which may be important in biological systems. Science. 1968;162:963–70.

    CAS  PubMed  Google Scholar 

  85. Remé CE, Malnoë A, Jung HH, Wei Q, Munz K. Effect of dietary fish oil on acute light-induced photoreceptor damage in the rat retina. Invest Ophthalmol Vis Sci. 1994;35:78–90.

    PubMed  Google Scholar 

  86. Richards MJ, Nagel BA, Fliesler SJ. Lipid hydroperoxide formation in the retina: correlation with retinal degeneration and light damage in a rat model of Smith–Lemli–Opitz syndrome. Exp Eye Res. 2006;82:538–41.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Wiegand RD, Joel CD, Rapp LM, Nielsen JC, Maude MB, Anderson RE. Polyunsaturated fatty acids and vitamin E in rat rod outer segments during light damage. Invest Ophthalmol Vis Sci. 1986;27:727–33.

    CAS  PubMed  Google Scholar 

  88. Li YZ, Tso MO, Wang HM, Organisciak DT. Amelioration of photic injury in rat retina by ascorbic acid. Invest Ophthalmol Vis Sci. 1985;26:1589–98.

    CAS  PubMed  Google Scholar 

  89. Organisciak DT, Wang HM, Li YZ, Tso MO. The protective effect of ascorbate in retinal light damage of rats. Invest Ophthalmol Vis Sci. 1985;26:1580–8.

    CAS  PubMed  Google Scholar 

  90. Organisciak DT, Bicknell IR, Darrow RM. The effects of l- and d- ascorbic acid administration on retinal tissue levels and light damage n rats. Curr Eye Res. 1992;11:231–41.

    CAS  PubMed  Google Scholar 

  91. Organisciak DT, Darrow RA, Barsalou L, Darrow RM, Lininger LA. Light-induced damage to the retina: differential effects of dimethylthiourea on photoreceptor survival, apoptosis and DNA. Photochem Photobiol. 1999;70:261–8.

    CAS  PubMed  Google Scholar 

  92. Thomson LR, Toyoda Y, Delori FC, Garnett KM, Wong ZY, Nichols CR, et al. Long term dietary supplementation with zeaxanthin reduces photoreceptor death in light-damaged Japanese quail. Exp Eye Res. 2002;75:529–42.

    CAS  PubMed  Google Scholar 

  93. Organisciak DT, Darrow RM, Rapp CM, Smuts JP, Armstrong DW, Lang JC. Prevention of retinal light damage by zinc oxide combined with rosemary extract. Mol Vis. 2013;19:1433–45.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Bai S, Sheline CT. NAD(+) maintenance attenuates light induced photoreceptor degeneration. Exp Eye Res. 2013;108:76–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Laabich A, Vissvesvaran GP, Lieu KL, Murata K, McGinn TE, Manmoto CC, et al. Protective effect of crocin against blue light- and white light-mediated photoreceptor cell death in bovine and primate retinal primary cell culture. Invest Ophthalmol Vis Sci. 2006;47:3156–63.

    PubMed  Google Scholar 

  96. Maccarone R, Di Marco S, Bisti S. Saffron supplement maintains morphology and function after exposure to damaging light in mammalian retina. Invest Ophthalmol Vis Sci. 2008;49:1254–61.

    PubMed  Google Scholar 

  97. Choi MY, Heo JH, Auh SJ, Yu YS. Effect of oxygen on photoreceptor degeneration in retinal degeneration mice. J Korean Ophthalmol Soc. 2000;41:1824–33.

    Google Scholar 

  98. Choi MY, Yu YS, Kim SK, Kim YJ, Seo JS. The effect of oxygen on retinal degeneration in wild-type and hsp70.1 knockout neonatal retinal degeneration mice. Korean J Ophthalmol. 2001;15:1–7.

    CAS  PubMed  Google Scholar 

  99. Valter K, Mervin K, Maslim J, Stone J. The influence of oxygen on the survival and death of photoreceptors: evidence from rat and mouse. In: LaVail MM, Hollyfield JG, Anderson RE, editors. Degenerative retinal diseases. New York: Plenum Press; 1997. p. 353–67.

  100. Valter K, Maslim J, Bowers F, Stone J. Photoreceptor dystrophy in the RCS rat: roles of oxygen, debris, and bFGF. Invest Ophthalmol Vis Sci. 1998;39:2427–42.

    CAS  PubMed  Google Scholar 

  101. D’Cruz PM, Yasumura D, Weir J, Matthes MT, Abderrahim H, LaVail MM, et al. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet. 2000;9:645–51.

    PubMed  Google Scholar 

  102. Gal A, Li Y, Thompson DA, Weir J, Orth U, Jacobson SG, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000;26:270–1.

    CAS  PubMed  Google Scholar 

  103. Nandrot E, Dufour EM, Provost AC, Péquignot MO, Bonnel S, Gogat K, et al. Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis. Neurobiol Dis. 2000;7:586–99.

    CAS  PubMed  Google Scholar 

  104. Bowes C, Li T, Danciger M, Baxter LC, Applebury ML, Farber DB. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature. 1990;347:677–80.

    CAS  PubMed  Google Scholar 

  105. Farber DB, Lolley RN. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science. 1974;186:449–51.

    CAS  PubMed  Google Scholar 

  106. Yu DY, Cringle SJ, Su EN, Yu PK. Intraretinal oxygen levels before and after photoreceptor loss in the RCS rat. Invest Ophthalmol Vis Sci. 2000;41:3999–4006.

    CAS  PubMed  Google Scholar 

  107. Stone J, Maslim J, Valter-Kocsi K, Mervin K, Bowers F, Chu Y, et al. Mechanisms of photoreceptor death and survival in mammalian retina. Prog Retin Eye Res. 1999;18:689–735.

    CAS  PubMed  Google Scholar 

  108. Hackam AS, Strom R, Liu D, Qian J, Wang C, Otteson D, et al. Identification of gene expression changes associated with the progression of retinal degeneration in the rd1 mouse. Invest Ophthalmol Vis Sci. 2004;45:2929–42.

    PubMed  Google Scholar 

  109. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems: recent advances. Prog Retin Eye Res. 1998;17:33–58.

    CAS  PubMed  Google Scholar 

  110. Geroski DH, Edelhauser HF. Drug delivery for posterior segment eye disease. Invest Ophthalmol Vis Sci. 2000;41:961–4.

    CAS  PubMed  Google Scholar 

  111. Wenzel A, Grimm C, Samardzija M, Remé CE. Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection for retinal degeneration. Prog Retin Eye Res. 2005;24:275–306.

    CAS  PubMed  Google Scholar 

  112. Wen R, Song Y, Cheng T, Matthes MT, Yasumura D, LaVail MM, et al. Injury-induced upregulation of bFGF and CNTF mRNAs in the rat retina. Neurosci. 1995;15:7377–85.

    CAS  Google Scholar 

  113. Cao W, Wen R, Li F, LaVail MM, Steinberg RH. Mechanical injury increases bFGF and CNTF mRNA expression in the mouse retina. Exp Eye Res. 1997;65:241–8.

    CAS  PubMed  Google Scholar 

  114. 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;12:3554–67.

    CAS  PubMed  Google Scholar 

  115. Abe T, Wakusawa R, Seto H, Asai N, Saito T, Nishida K. Topical doxycycline can induce expression of BDNF in transduced retinal pigment epithelial cells transplanted into the subretinal space. Invest Ophthalmol Vis Sci. 2008;49:3631–9.

    PubMed  Google Scholar 

  116. Liang FQ, Dejneka NS, Cohen DR, Krasnoperova NV, Lem J, Maguire AM, et al. AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival in the rhodopsin knockout mouse. Mol Ther. 2001;3:241–8.

    CAS  PubMed  Google Scholar 

  117. Cayouette M, Behn D, Sendtner M, Lachapelle P, Gravel C. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J Neurosci. 1998;18:9282–93.

    CAS  PubMed  Google Scholar 

  118. Loftsson T, Sigurdsson HH, Konradsdottir F, Gísladóttir S, Jansook P, Stefánsson E. Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations. Pharmazie. 2008;63:171–9.

    CAS  PubMed  Google Scholar 

  119. Maurice DM. Drug delivery to the posterior segment from drops. Surv Ophthalmol. 2002;47:S41–52.

    PubMed  Google Scholar 

  120. Colafrancesco V, Coassin M, Rossi S, Aloe L. Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration. Ann Ist Super Sanita. 2011;47:284–9.

    CAS  PubMed  Google Scholar 

  121. Lambiase A, Tirassa P, Micera A, Aloe L, Bonini S. Pharmacokinetics of conjunctivally applied nerve growth factor in the retina and optic nerve of adult rats. Invest Ophthalmol Vis Sci. 2005;46:3800–6.

    PubMed  Google Scholar 

  122. Lambiase A, Aloe L, Centofanti M, Parisi V, Mantelli F, Colafrancesco V, et al. Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: implications for glaucoma. Proc Natl Acad Sci U S A. 2009;106:13469–74.

    PubMed Central  CAS  Google Scholar 

  123. Lambiase A, Coassin M, Tirassa P, Mantelli F, Aloe L. Nerve growth factor eye drops improve visual acuity and electrofunctional activity in age related macular degeneration: a case report. Ann Ist Super Sanita. 2009;45:439–42.

    PubMed  Google Scholar 

  124. Falsini B, Chiaretti A, Barone G, Piccardi M, Pierri F, Colosimo C, et al. Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology. Neurorehabil Neural Repair. 2011;25:512–20.

    PubMed  Google Scholar 

  125. Edelhauser HF, Rowe-Rendleman CL, Robinson MR, Dawson DG, Chader GJ, Grossniklaus HE, et al. Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications. Invest Ophthalmol Vis Sci. 2010;51:5403–20.

    PubMed Central  PubMed  Google Scholar 

  126. Tao W, Wen R, Goddard MB, Sherman SD, O’Rourke PJ, Stabila PF, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002;43:3292–8.

    PubMed  Google Scholar 

  127. Tao W. Application of encapsulated cell technology for retinal degenerative diseases. Expert Opin Biol Ther. 2006;6:717–26.

    CAS  PubMed  Google Scholar 

  128. Tao W, Wen R. Application of encapsulated cell technology for retinal degenerative diseases. In: Tombran-Tink J, Barnstable CJ, editors. Retinal degenerations: biology, diagnositics, and therapeutics. Totowa: Humana Press; 2007. p. 401–13.

  129. Jiang J, Moore JS, Edelhauser HF, Prausnitz MR. Intrascleral drug delivery to the eye using hollow microneedles. Pharm Res. 2009;26:395–403.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Patel SR, Berezovsky DE, McCarey BE, Zarnitsyn V, Edelhauser HF, Prausnitz MR. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci. 2012;53:4433–41.

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Letizia Rufo for help in figure creation and editing. The authors have no conflicts of interest. The paper has not received any funding support.

Author contributions

Edoardo Abed: writing the article, literature search, guarantor for the overall content.

Giovanni Corbo: literature search.

Benedetto Falsini: idea for the review, critical revision of the article, final approval of the article.

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Abed, E., Corbo, G. & Falsini, B. Neurotrophin Family Members as Neuroprotectants in Retinal Degenerations. BioDrugs 29, 1–13 (2015). https://doi.org/10.1007/s40259-014-0110-5

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