title: Subconjunctival injection of XG-102, a c-Jun N-terminal kinase inhibitor peptide, in the treatment of endotoxin-induced uveitis in rats.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: 1 INSERM UMRS 1138, Team 17 from Physiopathology of Retinal Diseases to Clinical Developments , Paris, France .
authors.forename: Ikram
authors.initials: I
authors.lastname: El Zaoui
authors.forename: Elodie
authors.initials: E
authors.lastname: Touchard
authors.forename: Marianne
authors.initials: M
authors.lastname: Berdugo
authors.forename: Claire
authors.initials: C
authors.lastname: Abadie
authors.forename: Laura
authors.initials: L
authors.lastname: Kowalczuk
authors.forename: Catherine
authors.initials: C
authors.lastname: Deloche
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Naud
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Combette
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D056965:Injections, Intraocular; D007275:Injections, Intravenous; D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010455:Peptides / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D008070:Lipopolysaccharides; D010455:Peptides; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C478085:D-JNKI-1