Adipocyte-and macrophage-mediated inflammatory reactions by an atypical antipsychotic drug, olanzapine:effects on the production of nitric oxide and prostaglandin E2

초록

Atypical antipsy chotic drugs used for therapy of schizophrenia patients are known to increase the incidence of side effects like abnormal lipid metabolism causing weight gain, hyperlipidemia, and obesity-induced type II diabetes. Especially, nitric (NO) overproduced in the drug-induced inflammatory reactions may mediate the impaired lipid metabolism.We hypothesized that the olanzapine (OLZ)- and clozapine (CLZ)-induced adverse effects may be related with a low-grade systemic inflammatory reaction. Thus, we examined drug induced changes in the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and also the pathways involved in leptin production using the adipocyte and macrophage cell culture systems.We examined the leptin release from drug-treated 3T3-L1 cells. In addition, we examined whether the release of inflammatory mediators such as NO and PGE2 can be induced by interactions between leptin-releasing adipocytes (3T3-L1) and macrophages (RAW 264.7) after exposing them to some of the atypical antipsychotics. Results : After treatment of OLZ to the 3T3-L1 cells, release of leptin was increased in a dose-dependent manner. Production of NO and PGE2 increased significantly in RAW 264.7 cells activated with the conditioned media of OLZ or CLZ pretreated 3T3-L1 cell. But, there were no direct effects of OLZ or CLZ on the production of NO and PGE2 in both cell types. These results suggest that overproduced NO observed in immune cells is caused by the leptin released from the OLZ- and CLZ-activated adipocytes. This may lead to the drug-induced side effects like the weight gain, hypertriglyceridemia or the obesity-induced DM.