A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.

Details

Serval ID
serval:BIB_679B28AA5A30
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.
Journal
Investigative Ophthalmology and Visual Science
Author(s)
Touchard E., Omri S., Naud M.C., Berdugo M., Deloche C., Abadie C., Jonet L., Jeanny J.C., Crisanti P., de Kozak Y., Combette J.M., Behar-Cohen F.
ISSN
1552-5783 (Electronic)
ISSN-L
0146-0404
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
51
Number
9
Pages
4683-4693
Language
english
Notes
Publication types: Journal ArticlePublication Status: ppublish
Abstract
PURPOSE: To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU).
METHODS: EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues.
RESULTS: After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13.
CONCLUSIONS: This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.
Keywords
Animals, Chemokines/metabolism, Cytokines/metabolism, Disease Models, Animal, Down-Regulation/drug effects, Drug Combinations, Female, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/drug effects, Injections, Intraocular, Injections, Intravenous, JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases/metabolism, Lipopolysaccharides/toxicity, Nitric Oxide Synthase Type II/genetics, Nitric Oxide Synthase Type II/metabolism, Oils, Peptides/pharmacokinetics, Peptides/pharmacology, Phenols, Rats, Rats, Inbred Lew, Signal Transduction/drug effects, Tissue Distribution, Uveitis/chemically induced, Uveitis/drug therapy, Vitreous Body
Pubmed
Web of science
Open Access
Yes
Create date
23/08/2013 7:55
Last modification date
20/08/2019 14:23
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