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Topical treatment with nerve growth factor in an animal model of herpetic keratitis

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Abstract

Background

In vitro and in vivo studies demonstrated the antiviral efficacy of nerve growth factor (NGF) and its cyto-protective effect in herpes simplex virus (HSV)-infected cells. The aims of this study were to evaluate the role of endogenous NGF in HSV corneal infection, and the effects of topical NGF treatment on herpetic keratitis.

Methods

Herpetic keratitis was induced in 40 rabbits with the HSV-1 McKrae strain. Animals were divided into four groups, and treated with topical neutralizing anti-NGF antibodies, NGF, acyclovir or balanced salt solution (BSS) respectively. The clinical course of HSV keratitis was evaluated and scored by slit-lamp examination. In addition, biochemical (immunohistochemistry for glycoprotein D) and molecular (nested PCR for glycoprotein D) analyses were carried out to estimate viral replication.

Results

Treatment with anti-NGF antibodies induced a more severe keratitis associated with increased biochemical and molecular markers of active viral replication. Two animals in this group developed lethal HSV encephalitis. Conversely, topical treatment with NGF induced a significant amelioration of clinical and laboratory parameters when compared to the BSS treated group (control). No significant differences were observed between NGF- and acyclovir-treated groups.

Conclusions

This study demonstrated the crucial role of endogenous NGF in herpetic keratitis. The comparable effects of NGF and acyclovir confirm the antiviral activity of NGF, and indicate a potential use of topical NGF in herpetic keratitis.

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References

  1. Akbar AN, Lord JM, Salmon M (2000) IFN-alpha and IFN-beta: a link between immune memory and chronic inflammation. Immunol Today 21:337–342

    Article  PubMed  CAS  Google Scholar 

  2. Akova YA, Onat M, Duman S (1999) Efficacy of low-dose and long-term oral acyclovir therapy after penetrating keratoplasty for herpes simplex heratitis. Ocul Immunol Inflamm 7:51–60

    Article  PubMed  CAS  Google Scholar 

  3. Aloe L (1987) Intraocular herpes simplex virus injection in neonatal rats induces sympathetic nerve cell destruction: effect of nerve growth factor. Int J Dev Neurosci 5:357–366

    Article  PubMed  CAS  Google Scholar 

  4. Anand BS, Hill JM, Dey S, Maruyama K, Bhattacharjee PS, Myles ME, Nashed YE, Mitra AK (2003) In vivo antiviral efficacy of a dipeptide Acyclovir prodrug, val-val-Acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. IOVS 44:2529–2534

    Google Scholar 

  5. Arffa RC (1991) Epithelial diseases. In: Arffa RC (ed.) Grayson’s diseases of the cornea, 3rd edn. Mosby Inc, St. Louis

    Google Scholar 

  6. Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M (1991) Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 337:189–192

    Article  PubMed  CAS  Google Scholar 

  7. Barney NP, Foster CS (1994) A prospective randomized trial of oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Cornea 13:232–236

    Article  PubMed  CAS  Google Scholar 

  8. Barouch R, Kazimirsky G, Appel E, Brodie C (2001) Nerve growth factor regulates TNF-alpha production in mouse macrophages via MAP kinase activation. J Leukoc Biol 69:1019–1026

    PubMed  CAS  Google Scholar 

  9. Biswas S, Suresh P, Bonshek RE, Corbitt G, Tullo AB, Ridgway AE (2000) Graft failure in human donor corneas due to transmission of herpes simplex virus. Br J Ophthalmol 84:701–705

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L (2000) Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology 107:1347–1351

    Article  PubMed  CAS  Google Scholar 

  12. Bonneau RH, Sheridan JF, Feng N, Glaser R (1991) Stress-induced suppression of herpes simplex virus (HSV)-specific cytotoxic T lymphocyte and natural killer cell activity and enhancement of acute pathogenesis following local HSV infection. Brain Behav Immun 5:170–192

    Article  PubMed  CAS  Google Scholar 

  13. Coassin M, Lambiase A, Costa N, De Gregorio A, Sgrulletta R, Sacchetti M, Aloe L, Bonini S (2005) Efficacy of topical nerve growth factor treatment in dogs affected by dry eye. Graefes Arch Clin Exp Ophthalmol 243:151–155

    Article  PubMed  CAS  Google Scholar 

  14. Cocchi F, Fusco D, Menotti L, Gianni T, Eisenberg RJ, Cohen GH, Campanelli-Fiume G (2004) The solubile ectodomain of herpes simplex virus gD contains a membrane-proximal pro-fusion domain and suffices to mediate virus entry. Proc Natl Acad Sci USA 101:7445–7450

    Article  PubMed  CAS  Google Scholar 

  15. Cockerham G (2001) Primary graft failure caused by herpes simplex virus type 1. Cornea 20:774–775

    Article  PubMed  CAS  Google Scholar 

  16. Cook ML, Bastone VB, Stevens JG (1974) Evidence that neurons harbor latent herpes simplex virus. Infect Immun 9:946–951

    PubMed  CAS  Google Scholar 

  17. Cook SD (1992) Herpes simplex virus in the eye. Br J Ophthalmol 76:365–366

    Article  PubMed  CAS  Google Scholar 

  18. De Maria A, Tundo P, Romano A, Grima P (1995) Anti-HSV-1 herpes vaccination by LUPIDON H: preliminary results. Adv Exp Med Biol 371B:1599–1600

    PubMed  Google Scholar 

  19. Dicou E, Nerriere V, Labropoulou V (1991) Naturally occurring antibodies against nerve growth factor in human and rabbit sera: comparison between control and herpes simplex virus-infected patients. J Neuroimmunol 34:153–158

    Article  PubMed  CAS  Google Scholar 

  20. Ehrhard PB, Ganter U, Stalder A, Bauer J, Otten U (1993) Expression of functional trk protooncogene in human monocytes. Proc Natl Acad Sci USA 90:5423–5427

    Article  PubMed  CAS  Google Scholar 

  21. Gee AP, Boyle MD, Munger KL, Lawman MJ, Young M (1983) Nerve growth factor: stimulation of polymorphonuclear leukocyte chemotaxis in vitro. Proc Natl Acad Sci USA 80:7215–7218

    Article  PubMed  CAS  Google Scholar 

  22. Heise MT, Virgin HW (1995) The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol 69:904–909

    PubMed  CAS  Google Scholar 

  23. Herpetic Eye Disease Study Group (2000) Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol 118:1030–1036

    Google Scholar 

  24. Hill JM, Garza HH Jr, Helmy MF, Cook SD, Osborne PA, Johnson EM Jr, Thompson HW, Green LC, O’Callaghan RJ, Gebhardt BM (1997) Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits. J Neurovirology 3:206–211

    Article  CAS  Google Scholar 

  25. Johnson GL, Limon L, Trikha G, Wall H (1994) Acute renal failure and neurotoxicity following oral acyclovir. Ann Pharmacother 28:460–463

    PubMed  CAS  Google Scholar 

  26. Lalani AS, Barrett JW, McFadden G (2000) Modulating chemokines: more lessons from viruses. Immunol Today 21:100–106

    Article  PubMed  CAS  Google Scholar 

  27. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L (1998) Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med 338:1174–1180

    Article  PubMed  CAS  Google Scholar 

  28. 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 41:1063–1069

    PubMed  CAS  Google Scholar 

  29. Lambiase A, Bonini S, Rama P, Bonini S, Aloe L (2000) Antiinflammatory and healing properties of nerve growth factor in immune corneal ulcers with stromal melting. Arch Ophthalmol 118:1446–1449

    PubMed  CAS  Google Scholar 

  30. Laycock KA, Brady RH, Lee SF, Osborne PA, Johnson EM, Pepose JS (1994) The role of nerve growth factor in modulating herpes simplex virus reactivation in vivo. Graefes Arch Clin Exp Ophthalmol 232:421–425

    Article  PubMed  CAS  Google Scholar 

  31. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162

    Article  PubMed  CAS  Google Scholar 

  32. Levi-Montalcini R, Aloe L, Alleva E (1990) A role for nerve growth factor in nervous, endocrine and immune system. Progress In Neuroendocrinimmunology 3:1–10

    Google Scholar 

  33. Matsuda H, Coughlin MD, Bienenstock J, Denburg JA (1988) Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci USA 85:6508–6512

    Article  PubMed  CAS  Google Scholar 

  34. McLennan JL, Darby G (1980) Herpes simplex virus latency: the cellular location of virus in dorsal root ganglia and the fate of the infected cell following activation. J Gen Virol 51:233–243

    Article  PubMed  CAS  Google Scholar 

  35. Moyes AL, Sugar A, Musch DC, Barnes RD (1994) Antiviral therapy after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol 112:601–607

    PubMed  CAS  Google Scholar 

  36. Nja A, Purves D (1978) The effects of nerve growth factor and its antiserum on synapses in the superior cervical ganglion of the guinea-pig. J Physiol 277:53–75

    PubMed  CAS  Google Scholar 

  37. Otten U, Ehrhard P, Peck R (1989) Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci USA 86:10059–10063

    Article  PubMed  CAS  Google Scholar 

  38. Perry AK, Chen G, Zheng D, Tang H, Cheng G (2005) The host type I interferon response to viral and bacterial infections. Cell Res 15:407–422

    Article  PubMed  CAS  Google Scholar 

  39. Pivetti-Pezzi P, Accorinti M, Colabelli-Gisoldi RA, Pirraglia MP, Sirianni MC (1999) Herpes simplex virus vaccine in recurrent herpetic ocular infection. Cornea 18:47–51

    Article  PubMed  CAS  Google Scholar 

  40. Price RW, Schmitz J (1978) Reactivation of latent herpes simplex virus infection in autonomic nervous system by postganglionic neurectomy. Infect Immun 19:523–532

    PubMed  CAS  Google Scholar 

  41. Purves D, Nja A (1976) Effect of nerve growth factor on synaptic depression following axotomy. Nature 260:535–536

    Article  PubMed  CAS  Google Scholar 

  42. Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson D (1993) Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262:695–700

    Article  PubMed  CAS  Google Scholar 

  43. Rajcani J, Vojvodova A (1998) The role of herpes simplex glycoproteins in the virus replication cycle. Acta Virol 42:103–118

    PubMed  CAS  Google Scholar 

  44. Remeijer L, Osterhaus A, Verjans G (2004) Human herpes simplex virus keratitis: the pathogenesis revisited. Ocul Immunol Inflamm 12:255–285

    Article  PubMed  Google Scholar 

  45. Sawtell NM, Thompson RL (1992) Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia. J Virol 66:2150–2156

    PubMed  CAS  Google Scholar 

  46. Sedgwick JD, Riminton DS, Cyster JG, Korner H (2000) Tumor necrosis factor: a master-regulator of leukocyte movement. Immunol Today 21:110–113

    Article  PubMed  CAS  Google Scholar 

  47. Smith RL, Pizer LI, Johnson EM Jr, Wilcox CL (1992) Activation of second-messenger pathways reactivates latent herpes simplex virus in neuronal cultures. Virol 188:311–318

    Article  CAS  Google Scholar 

  48. Tambasco FP, Cohen EJ, Nguyen LH, Rapuano CJ, Laibson PR (1999) Oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol 117:445–449

    PubMed  CAS  Google Scholar 

  49. The Herpetic Eye Disease Study Group (1998) Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 339:300–306

    Article  Google Scholar 

  50. Thoenen H, Barde YA (1980) Physiology of nerve growth factor. Physiol Rev 60:1284–1335

    PubMed  CAS  Google Scholar 

  51. Thorpe LW, Perez-Polo JR (1987) The influence of nerve growth factor on the in vitro proliferative response of rat spleen lymphocytes. J Neurosci Res 18:134–139

    Article  PubMed  CAS  Google Scholar 

  52. Ungheri D, Verini MA, Ganceff L, Mazue G, Carminati P (1993) Antiviral activity of nerve growth factor in vitro. Drugs Exp Clin Res 19:151–157

    PubMed  CAS  Google Scholar 

  53. Vandepapeliere P (2002) Therapeutic vaccination against chronic viral infections. Lancet Infect Dis 2:353–367

    Article  PubMed  Google Scholar 

  54. Walz MA, Price RW, Notkins AL (1974) Latent ganglionic infection with herpes simplex virus types 1 and 2: viral reactivation in vivo after neurectomy. Science 184:1185–1187

    Article  PubMed  CAS  Google Scholar 

  55. Wilcox CL, Johnson EM (1987) Nerve growth factor deprivation results in the reactivation of latent herpes simplex virus in vitro. J Virol 61:2311–2315

    PubMed  CAS  Google Scholar 

  56. Wilcox CL, Johnson EM Jr (1988) Characterization of nerve growth factor-dependent herpes simplex virus latency in neurons in vitro. J Virol 62:393–399

    PubMed  CAS  Google Scholar 

  57. Wilcox CL, Smith RL, Freed CR, Johnson EM Jr (1990) Nerve growth factor-dependence of herpes simplex virus latency in peripheral sympathetic and sensory neurons in vitro. J Neurosci 10:1268–1275

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Ophthalmology, University Campus Bio-Medico of Rome, Via E. Longoni, 83 00155, Rome, Italy

    Alessandro Lambiase, Marco Coassin, Paolo Lauretti, Alessandra Micera, Emiliano Ghinelli & Stefano Bonini

  2. IRCCS-G.B. Bietti Eye Foundation, Rome, Italy

    Alessandra Micera

  3. Faculty of Pharmacy, University “Magna Grecia” of Catanzaro, Catanzaro, Italy

    Nicola Costa

  4. Institute of Neurobiology and Molecular Medicine, CNR-EBRI, Rome, Italy

    Luigi Aloe

  5. Ophthalmology Department, Scientific Institute San Raffaele Hospital, Milan, Italy

    Paolo Rama

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  1. Alessandro Lambiase
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  2. Marco Coassin
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  7. Luigi Aloe
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  9. Stefano Bonini
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Correspondence to Stefano Bonini.

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Lambiase, A., Coassin, M., Costa, N. et al. Topical treatment with nerve growth factor in an animal model of herpetic keratitis. Graefes Arch Clin Exp Ophthalmol 246, 121–127 (2008). https://doi.org/10.1007/s00417-007-0593-6

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  • DOI: https://doi.org/10.1007/s00417-007-0593-6

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