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

J Ocul Pharmacol Ther. 2015 Feb;31(1):17-24. doi: 10.1089/jop.2014.0019.


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.

MeSH terms

  • 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
  • Proto-Oncogene Proteins c-jun / metabolism
  • Random Allocation
  • Rats
  • Rats, Inbred Lew
  • Uveitis / chemically induced
  • Uveitis / drug therapy*
  • Uveitis / metabolism


  • 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