Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice Angelo O. Rosa a, ⁎ , 1 , Manuella P. Kaster b , Ricardo W. Binfaré b , Susana Morales c , Ester Martín-Aparicio c , Maria Luisa Navarro-Rico c , Ana Martinez c , Miguel Medina c , Antonio G. García a , Manuela G. López a , Ana Lúcia S. Rodrigues b a Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 28029, Madrid, Spain b Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Campus Universitário, Trindade-88040–900, Florianópolis-SC, Brazil c Neuropharma, Avenida de la industria 52, 28760 Tres Cantos, Madrid, Spain ABSTRACT ARTICLE INFO Article history: Received 31 October 2007 Received in revised form 20 May 2008 Accepted 22 May 2008 Available online 25 June 2008 Keywords: Antidepressant Forced swimming test Glycogen synthase kinase-3β Peroxisome proliferator-activated receptor gamma Thiadiazolidinone Glycogen synthase kinase-3β (GSK-3β) 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-3β inhibitor, and the well-established GSK-3β inhibitor AR- A014418 in the mouse forced swimming test (FST), a model widely used to evaluate antidepressant activity. We found that NP031115 had an IC 50 of 1.23 and 6.5 μM for GSK-3β and GSK-3α, 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 μg/site, i.c.v.), significantlyreduced 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 μM), AR-A014418 (1 μM), PG J2 (10 μM), and NP031115 (1,10 and 25 μM) activate PPARγ in CHO transfected cells. GW-9662 (10 μg/site, i.c.v, a PPARγ antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 μg/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 antidepressanteffect, likely by inhibiting GSK-3β and enhancing PPARγ activity. © 2008 Elsevier Inc. All rights reserved. 1. Introduction Current available antidepressants have frequent and persistent side effects. Another drawback is a delay of 3–6 weeks before their clinical effects can be achieved, and in many cases a lack of efficacy is observed (Nemeroff and Owens, 2002). For these reasons, new drugs as well as new targets for the treatment of depression are welcomed (Berton and Nestler, 2006). Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase found in all eukaryotes that was initially named for its ability to phosphorylate glycogen synthase, but it is now recognized as a key component of multiple signaling pathways (Jope and Roh, 2006). In mammals, two closely related isoforms, GSK- 3α and GSK-3β, are present. GSK-3β is highly expressed in neuronal tissue where its expression is regulated during development (Bhat et al., 2004). GSK-3β has been implicated in the mechanism of action of the mood stabilizers lithium and valproate (Chen et al., 1999; Li et al., 2002), largely used in the treatment of bipolar disorder (Jope, 1999). Furthermore, dysfunctional GSK-3β may also be involved in major depression (Jope and Roh, 2006). This involvement could be linked to the deficient serotonergic neurotransmission observed in depression (Berns and Nemeroff, 2003; Nestler et al., 2002), considering that serotonergic activity contributes to the inhibitory control of GSK-3β in mammalian brain in vivo (Li et al., 2004). This conclusion is based on the finding that serotonin (5-HT) itself, as well as fluoxetine (a selective serotonin re-uptake inhibitor) and 5-HT 1A agonists, aug- ment serine 9 phosphorylation with the consequent inhibition of GSK-3β (Li et al., 2004). AR-A014418, a specific inhibitor of GSK-3β, has an antidepressant-like effect in the forced swimming test (FST) (Gould et al., 2004) in rats, and L803-mts (N-myristoyl-GKEAP- PAPPQS(p)P), a novel GSK-3 peptide inhibitor, also produces an antidepressant-like effect in the mouse FST (Kaidanovich-Beilin et al., 2004). Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1549–1556 Abbreviations, ANOVA, analysis of variance, CDK, cyclin-dependent kinase, CHO, Chinese Hamster Ovary, FST, forced swimming test, GSK-3, glycogen synthase kinase-3, 5-HT, serotonin, 5-HT 1A , serotonin receptor sub-type 1A, LDH, lactate dehydrogenase, MAPK, mitogen activated protein kinase, PPAR, peroxisome proliferator-activated receptor, PKA, protein kinase A. ⁎ Corresponding author. Tel.: +1 301 4968994; fax: +1 301 4020074. E-mail address: angelo_oscar@hotmail.com (A.O. Rosa). 1 Present address: National Institutes of Health, NIA, BPMS, Bethesda, MD, United States. 0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2008.05.020 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnpbp