title: Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice.
abstract: Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed. Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades. We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins. In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities. VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis. VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit. The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects. The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning. Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. lipina@lunenfeld.ca
authors: Tatiana V
authors: TV
authors: Lipina
authors: Valle
authors: V
authors: Palomo
authors: Carmen
authors: C
authors: Gil
authors: Ana
authors: A
authors: Martinez
authors: John C
authors: JC
authors: Roder
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009433:Neural Inhibition / Q000187:drug effects; D018697:Nootropic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D013037:Spatial Behavior / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D011799:Quinazolines; D014230:Triazoles; D038362:Glycogen Synthase Kinase 3; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7