Subconjunctival injection of XG-102, a c-Jun N-terminal kinase inhibitor peptide, in the treatment of endotoxin-induced uveitis in rats.

Abstract

PURPOSE:

XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design.

METHODS:

EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot.

RESULTS:

XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina.

CONCLUSION:

These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.

• Authors: Ikram El Zaoui, Elodie Touchard, Marianne Berdugo, Claire Abadie, Laura Kowalczuk, Catherine Deloche, Min Zhao, Marie-Christine Naud, Jean-Marc Combette, Francine Behar-Cohen
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 31 Issue 1 Pg. 17-24 (Feb 2015) ISSN: 1557-7732 [Electronic] United States
• PMID: 25313830 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Chemokine CXCL1
• Cxcl1 protein, rat
• Lipopolysaccharides
• Peptides
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-jun
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• D-JNKI-1

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage)
• Chemokine CXCL1 (biosynthesis)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Female
• Injections, Intraocular
• Injections, Intravenous
• Lipopolysaccharides
• Nitric Oxide Synthase Type II (biosynthesis)
• Peptides (administration & dosage)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins c-jun (antagonists & inhibitors, metabolism)
• Random Allocation
• Rats
• Rats, Inbred Lew
• Uveitis (chemically induced, drug therapy, metabolism)