Abstract

Glycogen synthase kinase-3 beta (GSK-3 beta) is an enzyme that phosphorylates glycogen synthase, thereby inhibiting glycogen synthesis. Besides this role, it is now believed that this enzyme plays an important role in the pathophysiology of many brain diseases including depression. Some inhibitors of this enzyme have shown antidepressant effects in animal models. This study investigated the effects of a novel thiadiazolidinone NP031115, a putative GSK-3 beta inhibitor, and the well-established GSK-3 beta inhibitor AR-A014418 in the mouse forced swimming test (FST), a model widely used to evaluate antidepressant activity. We found that NP031115 had an IC50 of 1.23 and 6.5 mu M for GSK-3 beta and GSK-3 alpha, respectively. NP031115 (0.5 and 5 mg/kg, i.p.), in a way similar to imipramine (15 mg/kg, i.p), fluoxetine (32 mg/kg, i.p), AR-A014418 (9 mg/kg, i.p.), and rosiglitazone (5 mu g/site, i.c.v.). significantly reduced immobility time in the FST. NP031115 at the higher dose and AR-A014418 (9 mg/kg, i.p.) reduced locomotion in the open-field test. Rosiglitazone (30 mu M), AR-A014418 (1 mu M), PG(J2). (10 mu M), and NP031115 (1, 10 and 25 mu M) activate PPAR gamma in CHO transfected cells. GW-9662 (10 mu g/site, i.c.v, a PPAR gamma antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 mu g/site, i.c.v.) prevented the antidepressant-like effect of these drugs in the FST. The results of this study show that NP031115 can exhibit an antidepressant effect, likely by inhibiting GSK-3 beta and enhancing PPAR gamma activity. (C) 2008 Elsevier Inc. All rights reserved.