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Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model

  • Retinal Disorders
  • Published:
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Abstract

Background

Intravitreal injection of tissue plasminogen activator (tPA) is used to treat several ocular conditions, although excessive doses of intravitreal tPA cause retinal toxicity. Toxicity may increase in the ischemic retina, such as in central retinal vein occlusion (CRVO), because tPA toxicity to neural tissues increases under ischemic conditions. We investigated tPA toxicity to the retina in a CRVO rat model.

Methods

CRVO was induced in pigmented rats with rose Bengal-assisted laser photothrombosis. One hour after CRVO induction, 3 μl of tPA (0.075, 0.75, 3, or 7.5 μg) was injected intravitreally. Eyes that did not receive laser treatment, which served as non-CRVO controls, received tPA (0.75, 3, or 7.5 μg). The same amount of balanced salt solution (BSS) was injected as a nondrug control. Eyes were enucleated at 12 hours after injection, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining was performed to evaluate retinal cell apoptosis.

Results

The number of TUNEL-positive cells increased in a dose-dependent manner in both non-CRVO and CRVO group and significantly (P = 0.002) increased when 0.75, 3, or 7.5 μg of tPA was injected into the CRVO eyes. When comparing the number of TUNEL-positive cells between the eyes with and without CRVO that received the same treatment, apoptosis significantly increased in CRVO eyes.

Conclusions

Retinal toxicity associated with intravitreally injected tPA can increase in a dose-dependent manner and be exacerbated in CRVO eyes, suggesting that the dose of tPA should be reduced when tPA is used to treat eyes with CRVO.

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References

  1. Jaffe GJ, Abrams GW, Williams GA, Han DP (1990) Tissue plasminogen activator for postvitrectomy fibrin formation. Ophthalmology 97:184–189

    PubMed  CAS  Google Scholar 

  2. Lahey JM, Fong DS, Kearney J (1999) Intravitreal tissue plasminogen activator for acute central retinal vein occlusion. Ophthalmic Surg Lasers 30:427–434

    PubMed  CAS  Google Scholar 

  3. Glacet-Bernard A, Kuhn D, Vine AK, Oubraham H, Coscas G, Soubrane G (2000) Treatment of recent onset central retinal vein occlusion with intravitreal tissue plasminogen activator: a pilot study. Br J Ophthalmol 84:609–613

    Article  PubMed  CAS  Google Scholar 

  4. Elman MJ, Raden RZ, Carrigan A (2001) Intravitreal injection of tissue plasminogen activator for central retinal vein occlusion. Trans Am Ophthalmol Soc 99:219–223

    PubMed  CAS  Google Scholar 

  5. Kamei M, Tano Y, Maeno T, Ikuno Y, Mitsuda H, Yuasa T (1996) Surgical removal of submacular hemorrhage using tissue plasminogen activator and perfluorocarbon liquid. Am J Ophthalmol 121:267–275

    PubMed  CAS  Google Scholar 

  6. Johnson MW, Olsen KR, Hernandez E, Irvine WD, Johnson RN (1990) Retinal toxicity of recombinant tissue plasminogen activator in the rabbit. Arch Ophthalmol 108:259–263

    PubMed  CAS  Google Scholar 

  7. Min WK, Kim YB (1990) Resolution of experimental intravitreal fibrin by tissue plasminogen activator. Korean J Ophthalmol 4:58–65

    PubMed  CAS  Google Scholar 

  8. Irvin WD, Johnson MW, Hernandez E, Olsen KR (1991) Retinal toxicity of human tissue plasminogen activator in vitrectomized rabbit eyes. Arch Ophthalmol 109:718–722

    Google Scholar 

  9. Benner JD, Morse LS, Toth CA, Landers MB 3rd, Hjelmeland LM (1991) Evaluation of a commercial recombinant tissue-type plasminogen activator preparation in the subretinal space of the cat. Arch Ophthalmol 109:1731–1736

    PubMed  CAS  Google Scholar 

  10. Hrach CJ, Johnson MW, Hassan AS, Lei B, Sieving PA, Elner VM (2000) Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes. Arch Ophthalmol 118:659–663

    PubMed  CAS  Google Scholar 

  11. Oh HS, Kwon OW, Chung I, Lee SC, Koh HJ, Lee SH, Lee JH (2005) Retinal toxicity of commercial tissue plasminogen activator is mediated by the induction of nitric oxide in the mouse retinal primary cells. Curr Eye Res 30:291–297

    Article  PubMed  Google Scholar 

  12. Mali RS, Cheng M, Chintala SK (2005) Plasminogen activators promote excitotoxicity-induced retinal damage. FASEB J 19:1280–1289

    Article  PubMed  CAS  Google Scholar 

  13. Hesse L, Schmidt J, Kroll P (1999) Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 237:273–277

    Article  PubMed  CAS  Google Scholar 

  14. Chen SN, Yang TC, Ho CL, Kuo YH, Yip Y, Chao AN (2003) Retinal toxicity of intravitreal tissue plasminogen activator. Ophthalmology 110:704–708

    Article  PubMed  Google Scholar 

  15. Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA (1998) Tissue plasminogen activator increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 4:228–231

    Article  PubMed  CAS  Google Scholar 

  16. Liu D, Cheng T, Guo H, Fernandez JA, Griffin JH, Song X, Zlokovic BV (2004) Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 10:1379–1383

    Article  PubMed  CAS  Google Scholar 

  17. Jaffe GJ, Green GD, McKay BS, Hartz A, Williams GA (1988) Intravitreal clearance of tissue plasminogen activator in the rabbit. Arch Ophthalmol 106(7):969–972

    PubMed  CAS  Google Scholar 

  18. Kamei M, Misono K, Lewis H (1999) A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am J Ophthalmol 128(6):739–746

    Article  PubMed  CAS  Google Scholar 

  19. Ju WK, Kim KY, Park SJ, Park DK, Park CB, Oh SJ, Chung JW, Chun MH (2000) Nitric oxide is involved in sustained and delayed cell death of rat retina following transient ischemia. Brain Res 881:231–236

    Article  PubMed  CAS  Google Scholar 

  20. Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374

    Article  PubMed  CAS  Google Scholar 

  21. Royster AJ, Nanda SK, Hatchell DL, Tiedeman JS, Dutton JJ, Hatchell MC (1988) Photochemical initiation of thrombosis. Arch Ophthalmol 106:1608–1614

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, E7, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan

    Takuhiro Yamamoto, Motohiro Kamei, Paradee Kunavisarut, Mihoko Suzuki & Yasuo Tano

Authors
  1. Takuhiro Yamamoto
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  2. Motohiro Kamei
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  3. Paradee Kunavisarut
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  4. Mihoko Suzuki
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  5. Yasuo Tano
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Corresponding author

Correspondence to Motohiro Kamei.

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The authors have no proprietary interest in any aspect of this study.

Supported by a Grant-in-Aid for Scientific Research (#15591853) from the Ministry of Education, Science and Culture of Japan.

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Yamamoto, T., Kamei, M., Kunavisarut, P. et al. Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model. Graefes Arch Clin Exp Ophthalmol 246, 509–514 (2008). https://doi.org/10.1007/s00417-007-0670-x

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  • DOI: https://doi.org/10.1007/s00417-007-0670-x

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