title: Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats.
abstract: Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6weeks of chronic social isolation (CSIS), which causes depressive- and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-κB (NF-κB), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-κB nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-κB activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle- or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation.
authors.affiliation: Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Todorović
authors.affiliation: Institute of Pathology, School of Medicine, University of Belgrade, Serbia.
authors.forename: Nada
authors.initials: N
authors.lastname: Tomanović
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.affiliation: Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, Serbia. Electronic address: dragana@vinca.rs.
authors.forename: Dragana
authors.initials: D
authors.lastname: Filipović
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000077152:Olanzapine; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D012934:Social Isolation
chemical_list: D014150:Antipsychotic Agents; D016207:Cytokines; D016328:NF-kappa B; D001569:Benzodiazepines; D002374:Catalase; D005979:Glutathione Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D000077152:Olanzapine
keywords: Chronic social isolation; Histopathology; Inflammation; Liver; Olanzapine; Olanzapine (PubChem CID: 11163889); Oxidative stress