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Graefe's Archive for Clinical and Experimental Ophthalmology

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01-03-2017 | Basic Science

NGF/anti-VEGF combined exposure protects RCS retinal cells and photoreceptors that underwent a local worsening of inflammation

Authors: Maria Luisa Rocco, Bijorn Omar Balzamino, Graziana Esposito, Carla Petrella, Luigi Aloe, Alessandra Micera

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 3/2017

Abstract

Purpose

Our previous study highlighted the potential nerve growth factor (NGF) effect on damaged photoreceptors from a rat model of spontaneous Retinitis Pigmentosa (RP). Herein, we tested the combined NGF/anti-vascular endothelial growth factor (αVEGF) effect on cultured retinal cells isolated from Royal College of Surgeons (RCS) rats receiving an intravitreal VEGF injection (iv-VEGF) to exacerbate retinal inflammation/neovascularization.

Methods

RCS (n = 75) rats were equally grouped as untreated (n = 25), iv-saline (single saline intravitreal injection; n = 25) and iv-VEGF (single VEGF intravitreal injection; n = 25). Morphological and biochemical analysis or in vitro stimulations with the biomolecular investigation were carried out on explanted retinas. Isolated retinal cells were treated with NGF and αVEGF, either alone or in combination, for 6 days and cells were harvested for morphological and biomolecular analyses.

Results

Infiltrating inflammatory cells were detected in iv-VEGF exposed RCS retinas, indicative of exacerbated inflammation and neovascularization. In cell cultures, NGF/αVEGF significantly increased retinal cell survival as well as rhodopsin expression and neurite outgrowth in photoreceptors. Particularly, NGF/αVEGF upregulated Bcl-2 mRNA, downregulated Bax mRNA, upregulated trkA^NGFR mRNA and finally upregulated both NGF mRNA and protein.

Conclusions

These data confirm and extend our previous findings on NGF-photoreceptor crosstalk, highlighting that the NGF/αVEGF combination might be an interesting approach for improving neuroprotection of RCS retinal cells and likewise photoreceptors in the presence of neovascularization. Further studies are required to translate this in vitro approach into clinical practice.

Aloe L, Rocco ML, Balzamino BO, Micera A (2015) Nerve growth factor: a focus on neuroscience and therapy. Curr Neuropharmacol 13(3):294–303CrossRefPubMedPubMedCentral

Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO (2003) Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 22(1):1–29CrossRefPubMed

Okabe K, Kobayashi S, Yamada T et al (2014) Neurons limit angiogenesis by titrating VEGF in retina. Cell 159(3):584–596CrossRefPubMed

Rocco ML, Balzamino BO, Petrocchi Passeri P, Micera A, Aloe L (2015) Effect of purified murine NGF on isolated photoreceptors of a rodent developing retinitis pigmentosa. PLoS One 10(4), e0124810CrossRefPubMedPubMedCentral

Balzamino BO, Biamonte F, Esposito G, Marino R, Fanelli F, Keller F, Micera A (2014) Characterization of NGF, trkA (NGFR), and p75 (NTR) in retina of mice lacking reelin glycoprotein. Int J Cell Biol 2014:725928CrossRefPubMedPubMedCentral

Lambiase A, Aloe L, Mantelli F et al (2012) Capsaicin-induced corneal sensory denervation and healing impairment are reversed by NGF treatment. Invest Ophthalmol Vis Sci 53(13):8280–8287CrossRefPubMed

Micera A, Lambiase A, Stampachiacchiere B et al (2007) Nerve growth factor has a modulatory role on human primary fibroblast cultures derived from vernal keratoconjunctivitis-affected conjunctiva. Mol Vis 13:981–987PubMedPubMedCentral

Wang H, Wang R, Thrimawithana T, Little PJ, Xu J, Feng ZP, Zheng W (2014) The nerve growth factor signaling and its potential as therapeutic target for glaucoma. Biomed Res Int 2014:759473PubMedPubMedCentral

Balzamino BO, Esposito G, Marino R, Keller F, Micera A (2015) NGF expression in reelin-deprived retinal cells: a potential neuroprotective effect. Neuromol Med 17(3):314–325CrossRef

10.

Lambiase A, Tirassa P, Micera A, Aloe L, Bonini S (2005) Pharmacokinetics of conjunctivally applied nerve growth factor in the retina and optic nerve of adult rats. Invest Ophthalmol Vis Sci 46(10):3800–3806CrossRefPubMed

11.

Tomita H, Ishiguro S, Abe T, Tamai M (1998) Increased expression of low-affinity NGF receptor in rat retinal Müller cells after ischemia and reperfusion. Cell Struct Funct 23(4):201–207CrossRefPubMed

12.

Siliprandi R, Canella R, Carmignoto G (1993) Nerve growth factor promotes functional recovery of retinal ganglion cells after ischemia. Invest Ophthalmol Vis Sci 34(12):3232–3245PubMed

13.

Rudzinski M, Wong TP, Saragovi HU (2004) Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension. J Neurobiol 58(3):341–354CrossRefPubMed

14.

Mantelli F, Lambiase A, Colafrancesco V, Rocco ML, Macchi I, Aloe L (2014) NGF and VEGF effects on retinal ganglion cell fate: new evidence from an animal model of diabetes. Eur J Ophthalmol 24(2):247–253CrossRefPubMed

15.

Roberti G, Mantelli F, Macchi I, Massaro-Giordano M, Centofanti M (2014) Nerve growth factor modulation of retinal ganglion cell physiology. J Cell Physiol 229(9):1130–1133CrossRefPubMed

16.

Lambiase A, Aloe L, Centofanti M et al (2009) Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proc Natl Acad Sci U S A 106(32):13469–13474CrossRefPubMedPubMedCentral

17.

Coassin M, Lambiase A, Sposato V, Micera A, Bonini S, Aloe L (2008) Retinal p75 and bax overexpression is associated with retinal ganglion cells apoptosis in a rat model of glaucoma. Graefes Arch Clin Exp Ophthalmol 246(12):1743–1749CrossRefPubMed

18.

Sposato V, Bucci MG, Coassin M, Russo MA, Lambiase A, Aloe L (2008) Reduced NGF level and TrkA protein and TrkA gene expression in the optic nerve of rats with experimentally induced glaucoma. Neurosci Lett 446(1):20–24CrossRefPubMed

19.

Colafrancesco V, Parisi V, Sposato V et al (2011) Ocular application of nerve growth factor protects degenerating retinal ganglion cells in a rat model of glaucoma. J Glaucoma 20(2):100–108CrossRefPubMed

20.

Sondell M, Lundborg G, Kanje M (1999) Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 19(14):5731–5740PubMed

21.

Nishijima K, Ng YS, Zhong L et al (2007) Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 171(1):53–67CrossRefPubMedPubMedCentral

22.

Falk T, Zhang S, Sherman SJ (2009) Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson’s disease. Mol Neurodegener 4:49CrossRefPubMedPubMedCentral

23.

Campochiaro PA (2004) Ocular neovascularisation and excessive vascular permeability. Expert Opin Biol Ther 4(9):1395–1402CrossRefPubMed

24.

Miller JW (2016) VEGF: from discovery to therapy: the champalimaud award lecture. Transl Vis Sci Technol 5(2):9, eCollection 2016CrossRefPubMedPubMedCentral

25.

Cacciamani A, Parravano M, Scarinci F, Esposito G, Varano M, Micera A (2015) A simple spontaneous vitreal reflux collecting procedure during intravitreal injection: set-up and validation studies. Curr Eye Res 2015:1–6

26.

Kurihara T, Westenskow PD, Friedlander M (2014) Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signaling in the retina. Adv Exp Med Biol 801:275–281CrossRefPubMed

27.

Wang J, He C, Zhou T, Huang Z, Zhou L, Liu X (2016) NGF increases VEGF expression and promotes cell proliferation via ERK1/2 and AKT signaling in Müller cells. Mol Vis 22:254–263, eCollection 2016PubMedPubMedCentral

28.

Sornelli F, Lambiase A, Mantelli F, Aloe L (2010) NGF and NGF-receptor expression of cultured immortalized human corneal endothelial cells. Mol Vis 16:1439–1447PubMedPubMedCentral

29.

Malik A, Sood S, Narang S (2010) Successful treatment of choroidal neovascular membrane in retinitis pigmentosa with intravitreal bevacizumab. Int Ophthalmol 30(4):425–428CrossRefPubMed

30.

Yoshida N, Ikeda Y, Notomi S et al (2013) Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120:100–105CrossRefPubMed

31.

Chung H, Hwang JU, Kim JG, Yoon YH (2006) Optical coherence tomography in the diagnosis and monitoring of cystoid macular edema in patients with retinitis pigmentosa. Retina 26:922–927CrossRefPubMed

32.

Melo GB, Farah ME, Aggio FB (2007) Intravitreal injection of bevacizumab for cystoid macular edema in retinitis pigmentosa. Acta Ophthalmol Scand 85:461–463CrossRefPubMed

33.

Li Z, Wang J, Gao F et al (2016) Human adipose-derived stem cells delay retinal degeneration in royal college of surgeons rats through anti-apoptotic and VEGF-mediated neuroprotective effects. Curr Mol Med 16(6):553–566CrossRefPubMed

34.

Salom D, Diaz-Llopis M, García-Delpech S, Udaondo P, Sancho-Tello M, Romero FJ (2008) Aqueous humor levels of vascular endothelial growth factor in retinitis pigmentosa. Invest Ophthalmol Vis Sci 49(8):3499–3502CrossRefPubMed

35.

Lenzi L, Coassin M, Lambiase A, Bonini S, Amendola T, Aloe L (2005) Effect of exogenous administration of nerve growth factor in the retina of rats with inherited retinitis pigmentosa. Vis Res 45(12):1491–1500CrossRefPubMed

36.

Lambiase A, Mantelli F, Sacchetti M, Rossi S, Aloe L, Bonini S (2011) Clinical applications of NGF in ocular diseases. Arch Ital Biol 149(2):283–292PubMed

37.

Falsini B, Iarossi G, Chiaretti A et al (2016) NGF eye-drops topical administration in patients with retinitis pigmentosa, a pilot study. J Transl Med 14(1):8CrossRefPubMedPubMedCentral

38.

Yuzbasioglu E, Artunay O, Rasier R, Sengul A, Bahcecioglu H (2009) Intravitreal bevacizumab (Avastin) injection in retinitis pigmentosa. Curr Eye Res 34(3):231–237CrossRefPubMed

39.

Yoshida N, Ikeda Y, Notomi S et al (2013) Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120(1):e5–e12CrossRefPubMed

40.

Uliss AE, Gregor ZJ, Bird AC (1986) Retinitis pigmentosa and retinal neovascularization. Ophthalmology 93:1599–1603CrossRefPubMed

41.

Bocchini V, Angeletti PU (1969) The nerve growth factor: purification as a 30,000-molecular-weight protein. Proc Natl Acad Sci U S A 64(2):787–794CrossRefPubMedPubMedCentral

42.

Lambiase A, Centofanti M, Micera A et al (1997) Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal damage induced in rabbit by experimental ocular hypertension. Graefes Arch Clin Exp Ophthalmol 235(12):780–785CrossRefPubMed

43.

Aloe L, Fiore M, Santucci D et al (2001) Effect of hypergravity on the mouse basal expression of NGF and BDNF in the retina, visual cortex and geniculate nucleus: correlative aspects with NPY immunoreactivity. Neurosci Lett 302(1):29–32CrossRefPubMed

44.

Lambiase A, Coassin M, Costa N et al (2008) Topical treatment with nerve growth factor in an animal model of herpetic keratitis. Graefes Arch Clin Exp Ophthalmol 246(1):121–127CrossRefPubMed

45.

Liu Y, Yang X, Utheim TP et al (2013) Correlation of cytokine levels and microglial cell infiltration during retinal degeneration in RCS rats. PLoS One 8(12), e82061CrossRefPubMedPubMedCentral

46.

Zhang T, Wei Y, Jiang X, Li J, Qiu S, Zhang S (2015) Protection of photoreceptors by intravitreal injection of the Y-27632 Rho-associated protein kinase inhibitor in royal college of surgeons rats. Mol Med Rep 12(3):3655–3661PubMed

47.

Nickells RW, Zack DJ (1996) Apoptosis in ocular disease: a molecular overview. Ophthalmic Genet 17(4):145–165CrossRefPubMed

48.

Cuenca N, Fernández-Sánchez L, Campello L et al (2014) Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 43:17–75CrossRefPubMed

49.

Micera A, Vigneti E, Pickholtz D et al (2001) Nerve growth factor displays stimulatory effects on human skin and lung fibroblasts, demonstrating a direct role for this factor in tissue repair. Proc Natl Acad Sci U S A 98(11):6162–6167CrossRefPubMedPubMedCentral

50.

Fink DM, Connor AL, Kelley PM, Steele MM, Hollingsworth MA, Tempero RM (2014) Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution. PLoS One 9(11), e112737CrossRefPubMedPubMedCentral

51.

Lambiase A, Manni L, Bonini S, Rama P, Micera A, Aloe L (2000) Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 41(5):1063–1069PubMed

52.

Micera A, Lambiase A, Puxeddu I et al (2006) Nerve growth factor effect on human primary fibroblastic-keratocytes: possible mechanism during corneal healing. Exp Eye Res 83(4):747–757CrossRefPubMed

53.

Anitua E, Muruzabal F, Alcalde I, Merayo-Lloves J, Orive G (2013) Plasma rich in growth factors (PRGF-Endoret) stimulates corneal wound healing and reduces haze formation after PRK surgery. Exp Eye Res 115:153–161CrossRefPubMed

54.

Aloe L, Tirassa P, Lambiase A (2008) The topical application of nerve growth factor as a pharmacological tool for human corneal and skin ulcers. Pharmacol Res 57(4):253–258CrossRefPubMed

55.

Jones BW, Pfeiffer RL, Ferrell WD, Watt CB, Marmor M, Marc RE (2016) Retinal remodeling in human retinitis pigmentosa. Exp Eye Res 150:149–165CrossRefPubMed

56.

Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM (1990) Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 347(6288):83–86CrossRefPubMed

57.

Whiteley SJ, Klassen H, Coffey PJ, Young MJ (2001) Photoreceptor rescue after low-dose intravitreal IL-1beta injection in the RCS rat. Exp Eye Res 73(4):557–568CrossRefPubMed

58.

Ahn SJ, Kim KE, Woo SJ, Park KH (2014) The effect of an intravitreal dexamethasone implant for cystoid macular edema in retinitis pigmentosa: a case report and literature review. Ophthalmic Surg Lasers Imaging Retina 45(2):160–164CrossRefPubMed

Title: NGF/anti-VEGF combined exposure protects RCS retinal cells and photoreceptors that underwent a local worsening of inflammation
Authors: Maria Luisa Rocco
Bijorn Omar Balzamino
Graziana Esposito
Carla Petrella
Luigi Aloe
Alessandra Micera
Publication date: 01-03-2017
Publisher: Springer Berlin Heidelberg
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 3/2017
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-016-3567-8

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

NGF/anti-VEGF combined exposure protects RCS retinal cells and photoreceptors that underwent a local worsening of inflammation

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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