title: Inhibitory effect of aminoimidazole carboxamide ribonucleotide (AICAR) on endotoxin-induced uveitis in rats.
abstract: PURPOSE. To investigate the anti-inflammatory effect of aminoimidazole carboxamide ribonucleotide (AICAR), an analog of adenosine monophosphate (AMP), in endotoxin-induced uveitis (EIU). METHODS. EIU was induced by subcutaneous injection of lipopolysaccharide (LPS) (200 μg) in Lewis rats. AICAR (50 mg/kg, intraperitoneally) was given 6 hours prior and at the same time as LPS injection. Clinical uveitis scores, number of anterior chamber (AC) infiltrating cells, anterior chamber protein concentration, retinal vessel leukocyte adhesion, and protein leakage were measured 24 hours later. Protein levels of C-C chemokine ligand-2 (CCL-2)/monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) in aqueous humor and retina and nuclear translocation of nuclear factor-κB (NF-κB) in the retina were determined by enzyme-linked immunosorbent assay (ELISA). Both mRNA and protein levels of CD14 in peripheral blood mononuclear cells were also measured. RESULTS. AICAR treatment significantly reduced EIU clinical severity as well as inflammatory cell infiltration and protein concentration in aqueous humor. Similarly, the number of retinal vessel-adherent leukocytes and protein leakage were decreased by AICAR treatment. Protein levels of TNF-α, CCL-2/MCP-1, and ICAM-1 in aqueous humor and CCL-2/MCP-1 and ICAM-1 levels in retina were suppressed with AICAR treatment. AICAR also reduced NF-κB translocation and CD14 expression. CONCLUSIONS. AICAR reduces systemic LPS susceptibility and attenuates intraocular inflammation in a rat EIU model by limiting infiltration of leukocytes, suppressing inflammatory mediators, and inhibiting the NF-κB pathway.
authors.affiliation: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Akrivi
authors.initials: A
authors.lastname: Manola
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morizane
authors.forename: Kimio
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Maki
authors.initials: M
authors.lastname: Kayama
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Lucia
authors.initials: L
authors.lastname: Sobrin
authors.forename: Demetrios G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000867:Anterior Chamber / Q000473:pathology; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001082:Aqueous Humor / Q000378:metabolism; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012160:Retina / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012265:Ribonucleotides / Q000627:therapeutic use*; D012486:Salmonella typhimurium; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014606:Uveitis, Anterior / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide