Abstract
Purpose: :
To investigate the anti-inflammatory effect of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), stimulator of AMP-activated protein kinase, in endotoxin-induced uveitis (EIU) in rats and to elucidate the underlying molecular mechanisms.
Methods: :
EIU was induced by subcutaneous injection of lipopolysaccharide (LPS) (200 υg) in Lewis rats. Treatment group received AICAR (50mg/kg, intraperioneally), 6 hours prior and at the same time as LPS injection. After 24 hours, clinical uveitis scores were measured and aqueous humor was analyzed for leukocytes/ml and protein concentration. Leukocyte adhesion in the retinal vasculature was also measured. In addition, protein levels in the aqueous humor and whole retina were determined by ELISA for C-C chemokine ligand (CCL)2/ monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-alfa and intercellular adhesion molecule (ICAM)-1.
Results: :
EIU clinical severity was significantly reduced in AICAR treated animals (3.7 ± 0.7 vs 2.4 ± 0.6, p<0.01) as were inflammatory cell infiltration and protein concentration in aqueous humor (11.6 ± 14.7 vs 1.5 ± 1.6x105 cells/ml; 17.8 ± 10.4 vs 7.8 ± 6.7 mg/ml, respectively, p<0.05). Similarly, the number of leukocytes adherent to retinal vessels was reduced (1161.6 ± 243.6 vs 575.5 ± 248.5 cells/retina, p<0.001) and protein levels of TNF-alfa, CCL2/MCP-1 and ICAM-1 in aqueous humor and CCL2/MCP-1 and ICAM-1 levels in retina were suppressed with treatment with AICAR.
Conclusions: :
AICAR attenuates EIU progression by limiting infiltration of leukocytes and suppressing the production of inflammatory cytokines.
Keywords: uveitis-clinical/animal model • inflammation • adenosine