Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice.
Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta inhibitor, and the well-established GSK-3beta 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 microM for GSK-3beta and GSK-3alpha, 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 microg/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 microM), AR-A014418 (1 microM), PG(J2) (10 microM), and NP031115 (1, 10 and 25 microM) activate PPARgamma in CHO transfected cells. GW-9662 (10 microg/site, i.c.v, a PPARgamma antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 microg/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-3beta and enhancing PPARgamma activity.
Rosa
Angelo O
AO
Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo 4, 28029, Madrid, Spain. angelo_oscar@hotmail.com
Kaster
Manuella P
MP
Binfaré
Ricardo W
RW
Morales
Susana
S
Martín-Aparicio
Ester
E
Navarro-Rico
Maria Luisa
ML
Martinez
Ana
A
Medina
Miguel
M
García
Antonio G
AG
López
Manuela G
MG
Rodrigues
Ana Lúcia S
AL
D000818:Animals; D000928:Antidepressive Agents; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009043:Motor Activity / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D013550:Swimming / Q000523:psychology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D047495:PPAR gamma; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3