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Depression associating patients with chronic liver diseases is a major treatment goal. This study aimed to evaluate the potential hepatoprotective and antidepressant effects of celecoxib in a model of experimental autoimmune hepatitis (EAH) and depressive-like behavior in C57BL/6 mice.EAH was induced by immunization with S-100 liver antigen emulsified in complete Freund's adjuvant (CFA). Mice were randomly allocated to 5 groups; control phosphate buffered saline group; control CFA group; EAH group, and 2 groups of EAH plus celecoxib (7.5 or 15 mg/kg/d respectively). Mice were assessed behaviorally by novelty-suppressed test, tail suspension test, locomotor assessment and forced swimming tests. Serum liver enzymes and hepatic hydroxyproline content were biochemically analyzed. Histopathological analysis for liver and brain sections and immunohistochemical studies for hepatic and hippocampal tumor necrosis factor (TNF-α), nuclear factor Kappa-B (NF-κB) and caspase-3 were performed.EAH group exhibited significant depressive-like changes, increase in liver enzymes and hepatic hydroxyproline content. Signs of autoimmune hepatitis and structural changes in hippocampus were confirmed by histopathological studies. Immunohistochemical examination revealed overexpression of hepatic and hippocampal TNF-α, NF-κB and caspase-3 positive cells. Celecoxib (7.5 mg/kg/d) significantly ameliorated hepatic biochemical changes, hepatic and hippocampal histopathological and immunohistochemical changes induced in EAH group. Celecoxib (15 mg/kg/d) significantly ameliorated the behavioral changes, histopathological and immunohistochemical changes in hippocampus, with non-significant change in hepatic biochemical profile, histopathological and immunohistochemical changes induced in EAH group.The celecoxib (7.5 mg/kg/d) through its anti-inflammatory effect may represent a new therapeutic approach to treat autoimmune hepatitis associated with depressive symptoms.