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Effects of a selective glucocorticoid receptor agonist on experimental keratoplasty

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Abstract

Background

New insights into the molecular mechanisms of corticosteroid-mediated actions have revealed new substances, such as selective glucocorticoid receptor agonists (SEGRA), for the treatment of inflammatory diseases. We set out to evaluate the effect of a SEGRA compound following topical application on the course of experimental orthotopic corneal grafts.

Methods

A total of 42 female Lewis rats received 3.5-mm MHC I/II-incompatible corneal grafts from DA donors. Recipients were randomly assigned to receive either no therapy, 0.25% cyclodextrin-encapsulated SEGRA compound in a new microemulsion formulation or carrier system only. All treatments started on the day of surgery and were given five times daily for 35 days. Grafts were graded every day and a rejection score was generated based on cornea clarity and edema. In addition, intragraft mRNA expression of CD3, IFN-γ, TNF-α, IL-10 and IL-4 was analyzed using real-time RT-PCR analysis at day 7 after transplantation before rejection occurred in additional control animals.

Results

Topical application of a SEGRA compound was highly effective in prolonging the mean survival time of corneal grafts (42.2±4.0 days) compared with untreated controls (11.7±1.2 days, p=0.00003) or animals that received the vehicle only (15.0±1.5 days, p=0.114). In addition, real-time RT-PCR analysis of SEGRA-treated grafts revealed lower mRNA expression of intragraft cytokines; the difference was significant for IL-4 (p<0.05).

Conclusions

Our results indicate that topical application of a SEGRA compound significantly prolongs corneal graft survival in an experimental keratoplasty model. It further suggests that SEGRA can be a potentially useful drug to suppress the immune response.

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Authors and Affiliations

  1. Department of Ophthalmology, Institute of Pharmacy, Charité, Humboldt University, Berlin, Germany

    Uwe Pleyer, Jun Yang, Sigrid Knapp, Natasa Orlic, Ljijana Otasevic, Maurice De Ruijter & Sigrid Keipert

  2. Augenklinik, Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Uwe Pleyer

  3. Schering AG, Berlin, Germany

    Heike Schäcke & Norbert Schmees

  4. Institute of Medical Immunology, Charité, Humboldt University, Berlin, Germany

    Thomas Ritter

Authors
  1. Uwe Pleyer
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  2. Jun Yang
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  3. Sigrid Knapp
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  4. Heike Schäcke
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  6. Natasa Orlic
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  7. Ljijana Otasevic
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  8. Maurice De Ruijter
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  10. Sigrid Keipert
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Correspondence to Uwe Pleyer.

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Pleyer, U., Yang, J., Knapp, S. et al. Effects of a selective glucocorticoid receptor agonist on experimental keratoplasty. Graefe's Arch Clin Exp Ophthalmol 243, 450–455 (2005). https://doi.org/10.1007/s00417-004-0991-y

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  • DOI: https://doi.org/10.1007/s00417-004-0991-y

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