title: The prolyl oligopeptidase inhibitor IPR19 ameliorates cognitive deficits in mouse models of schizophrenia.
abstract: Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia.
authors.affiliation: Iproteos SL, Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Prades
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, BioCruces Health Research Institute, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Munarriz-Cuezva
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, BioCruces Health Research Institute, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Urigüen
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, BioCruces Health Research Institute, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Gil-Pisa
authors.affiliation: Iproteos SL, Barcelona, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Gómez
authors.affiliation: Iproteos SL, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Mendieta
authors.affiliation: Iproteos SL, Barcelona, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Royo
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Department of Organic Chemistry, University of Barcelona, Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
authors.affiliation: Iproteos SL, Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. Electronic address: teresa.tarrago@iproteos.com.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tarragó
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, BioCruces Health Research Institute, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain. Electronic address: javier.meana@ehu.eus.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011070:Poly I-C; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D000085822:Prolyl Oligopeptidases; D011619:Psychotropic Drugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D012565:Schizophrenic Psychology; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity
chemical_list: C000625936:IPR19 compound; D011619:Psychotropic Drugs; D015842:Serine Proteinase Inhibitors; D011392:Proline; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D011070:Poly I-C
keywords: Animal model; Cognition; Peptidomimetic; Prolyl oligopeptidase; Schizophrenia