Skip to main content

Advertisement

SpringerLink
Log in

The effect of thalidomide on vascular endothelial growth factor and tumor necrosis factor-α levels in retinal ischemia/reperfusion injury

  • Retinal Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Background

To evaluate the effects of thalidomide treatment on the temporal course of TNF-α, VEGF production and the histopathological changes in ischemia/reperfusion (I/R) injured guinea pigs retina.

Methods

Control, ischemia, and thalidomide/ischemia groups including seven animals each were formed. Retinal ischemia was induced in male guinea pigs by cannulating anterior chambers and lifting the bottle to a height of 205 cm for 90 min in the ischemia and thalidomide/ischemia groups. The thalidomide/ischemia group received thalidomide (300 mg/kg/day) via nasogastric tube 24 h before ischemia and during 7 days of reperfusion. Guinea pigs were sacrificed for histopathological examination to evaluate the mean thickness of the inner plexiform layer (IPL), polymorphonuclear leukocyte (PMNL) infiltration, and biochemical analysis of retinal VEGF and TNF-α levels by ELISA.

Results

The mean retinal VEGF and TNF-α levels of the control, ischemia, and thalidomide/ischemia groups were 10.22 ± 2.58 and 270.41 ± 69.77 pg/ml; 35.80 ± 5.97 and 629.93 ± 146.41 pg/ml; 19.01 ± 3.01 and 340.93 ± 158.26 pg/ml, respectively. The retinal VEGF levels were significantly higher in I/R injured groups. The thalidomide/ischemia group retinal VEGF level was significantly lower versus the ischemia group. The retinal TNF-α levels were significantly elevated in the ischemia group, but no difference was observed between the thalidomide/ischemia and control groups. Also, the retinal TNF-α level was significantly lower in the thalidomide/ischemia group versus the ischemia group. The mean thickness of IPL and PMNL infiltration showed no difference between the control and thalidomide/ischemia groups. However, there was a significant difference between the control and ischemia groups.

Conclusion

Thalidomide treatment decreases PMNL infiltration, retinal edema, VEGF, and TNF-α synthesis following I/R injury to the guinea pig retina.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hangai M, Yoshimura N, Honda Y (1996) Increased cytokine gene expression in rat retina following transient ischemia. Ophthalmic Res 28:248–254

    Article  PubMed  CAS  Google Scholar 

  2. Ogata N, Yamanaka R, Yamamoto C, Miyashiro M, Kimoto T, Takahashi K, Maruyama K, Uyama M (1998) Expression of vascular endothelial growth factor and its receptor, KDR, following retinal ischemia-reperfusion injury in the rat. Curr Eye Res 17:1087–1096

    Article  PubMed  CAS  Google Scholar 

  3. Chen CH, Chen SC (1987) Evidence of the presence of a specific vascular endothelial growth factor in fetal bovine retina. Exp Cell Res 169:287–295

    Article  PubMed  CAS  Google Scholar 

  4. Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1:182–193

    PubMed  CAS  Google Scholar 

  5. Hofman P, van Blijswijk BC, Gaillard PJ, Vrensen GF, Schlingemann RO (2001) Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Arch Ophthalmol 119:861–866

    PubMed  CAS  Google Scholar 

  6. Avery RL (2006) Regression of retinal and iris neovascularization after Intravitreal bevacizumab (Avastin) treatment. Retina 26:352–354

    Article  PubMed  Google Scholar 

  7. Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P (1987) Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA 84:5277–5281

    Article  PubMed  CAS  Google Scholar 

  8. Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N (1987) Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329:630–632

    Article  PubMed  CAS  Google Scholar 

  9. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  PubMed  CAS  Google Scholar 

  10. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934

    PubMed  CAS  Google Scholar 

  11. Majka S, McGuire PG, Das A (2002) Regulation of matrix metalloproteinase expression by tumor necrosis factor in a murine model of retinal neovascularization. Invest Ophthalmol Vis Sci 43:260–266

    PubMed  Google Scholar 

  12. Derevjanik NL, Vinores SA, Xiao WH, Mori K, Turon T, Hudish T, Dong S, Campochiaro PA (2002) Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci 43:2462–2467

    PubMed  Google Scholar 

  13. Sheskin J (1965) Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther 6:303–306

    PubMed  CAS  Google Scholar 

  14. D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082–4085

    Article  PubMed  CAS  Google Scholar 

  15. George A, Marziniak M, Schafers M, Toyka KV, Sommer C (2000) Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. Pain 88:267–275

    Article  PubMed  CAS  Google Scholar 

  16. Hughes WF (1991) Quantitation of ischemic damage in the rat retina. Exp Eye Res 53:573–582

    Article  PubMed  CAS  Google Scholar 

  17. Szabo ME, Droy-Lefaix MT, Doly M, Carre C, Braquet P (1991) Ischemia and reperfusion-induced histologic changes in the rat retina. Demonstration of a free radical mediated mechanism. Invest Ophthalmol Vis Sci 32:1471–1478

    PubMed  CAS  Google Scholar 

  18. Shima DT, Adamis AP, Ferrara N, Yeo KT, Yeo TK, Allende R, Folkman J, D’Amore PA (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1:182–193

    PubMed  CAS  Google Scholar 

  19. Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544

    PubMed  CAS  Google Scholar 

  20. Kenyon BM, Browne F, D’Amato RJ (1997) Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 64:971–978

    Article  PubMed  CAS  Google Scholar 

  21. Yabu T, Tomimoto H, Taguchi Y, Yamaoka S, Igarashi Y, Okazaki T (2005) Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate. Blood 106:125–134

    Article  PubMed  CAS  Google Scholar 

  22. Komorowski J, Jerczynska H, Siejka A, Baranska P, Lawnicka H, Pawlowska Z, Stepien H (2006) Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells. Life Sci 78:2558–2563

    Article  PubMed  CAS  Google Scholar 

  23. Yuan L, Neufeld AH (2000) Tumor necrosis factor-alpha: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia 32:42–50

    Article  PubMed  CAS  Google Scholar 

  24. Geyer O, Almog J, Lupu-Meiri M, Lazar M, Oron Y (1995) Nitric oxide synthase inhibitors protect rat retina against ischemic injury. FEBS Lett 374:399–402

    Article  PubMed  CAS  Google Scholar 

  25. Hangai M, Yoshimura N, Hiroi K, Mandai M, Honda Y (1996) Inducible nitric oxide synthase in retinal ischemia-reperfusion injury. Exp Eye Res 63:501–509

    Article  PubMed  CAS  Google Scholar 

  26. Lee JS, Kang Decker N, Chatterjee S, Yao J, Friedman S, Shah V (2005) Mechanisms of nitric oxide interplay with Rho GTPase family members in modulation of actin membrane dynamics in pericytes and fibroblasts. Am J Pathol 166:1861–1870

    PubMed  CAS  Google Scholar 

  27. Lopez-Talavera JC, Cadelina G, Olchowski J, Merrill W, Groszmann RJ (1996) Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats. Hepatology 23:1616–1621

    PubMed  CAS  Google Scholar 

  28. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G (1993) Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 177:1675–1680

    Article  PubMed  CAS  Google Scholar 

  29. Warren JS (1990) Interleukins and tumor necrosis factor in inflammation. Crit Rev Clin Lab Sci 28:37–59

    Article  PubMed  CAS  Google Scholar 

  30. Dunzendorfer S, Schratzberger P, Reinisch N, Kahler CM, Wiedermann CJ (1997) Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine-and endotoxin-activated endothelium. Naunyn Schmiedebergs Arch Pharmacol 356:529–535

    Article  PubMed  CAS  Google Scholar 

  31. Majumdar S, Lamothe B, Aggarwal BB (2002) Thalidomide suppresses NF-kappa B activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. J Immunol 168:2644–2651

    PubMed  CAS  Google Scholar 

  32. Yasui K, Kobayashi N, Yamazaki T, Agematsu K (2005) Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des 11:395–401

    Article  PubMed  CAS  Google Scholar 

  33. Schroder JM, Sellhaus B, Wohrmann T, Kogel B, Zwingenberger K (1995) Inhibitory effects of thalidomide on cellular proliferation, endoneurial edema and myelin phagocytosis during early wallerian degeneration. Acta Neuropathol (Berl) 89:415–419

    Article  CAS  Google Scholar 

Download references

Acknowledgement

The author has full control of all primary data and agrees to allow Graefe’s Archive to review the data upon request.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Fırat University School of Medicine, Elazığ, Turkey

    Semih Aydoğan, Ülkü Çeliker & Peykan Türkçüoğlu

  2. Department of Biochemistry, Fırat University School of Medicine, Elazığ, Turkey

    Nevin İlhan

  3. Department of Pathology, Fırat University School of Medicine, Elazığ, Turkey

    Nusret Akpolat

Authors
  1. Semih Aydoğan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ülkü Çeliker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peykan Türkçüoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nevin İlhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nusret Akpolat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peykan Türkçüoğlu.

Additional information

This study supported by Firot University Research Fund.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aydoğan, S., Çeliker, Ü., Türkçüoğlu, P. et al. The effect of thalidomide on vascular endothelial growth factor and tumor necrosis factor-α levels in retinal ischemia/reperfusion injury. Graefes Arch Clin Exp Ophthalmol 246, 363–368 (2008). https://doi.org/10.1007/s00417-007-0663-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-007-0663-9

Keywords

Search

Navigation