Effects of a selective glucocorticoid receptor agonist on experimental keratoplasty.
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-gamma, TNF-alpha, 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.
Pleyer
Uwe
U
Department of Ophthalmology, Institute of Pharmacy, Charité, Humboldt University, Berlin, Germany. uwe.pleyer@charite.de
Yang
Jun
J
Knapp
Sigrid
S
Schäcke
Heike
H
Schmees
Norbert
N
Orlic
Natasa
N
Otasevic
Ljijana
L
De Ruijter
Maurice
M
Ritter
Thomas
T
Keipert
Sigrid
S
D000287:Administration, Topical; D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D003505:Cyclodextrins; D004337:Drug Carriers; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage*; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D015948:Keratoplasty, Penetrating; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D017252:CD3 Complex; D003505:Cyclodextrins; D004337:Drug Carriers; D006574:Heterocyclic Compounds, 2-Ring; D006846:Hydrocarbons, Halogenated; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma