title: The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia.
abstract: D-Amino acid oxidase (DAO) has been established to be involved in the oxidation of D-serine, an allosteric activator of the N-methyl-D-aspartate-type glutamate receptor in the brain, and to be associated with the onset of schizophrenia. The effect of risperidone, a benzisoxazole derivative, atypical antischizophrenic drug, on the activity of human DAO was tested using an in-vitro oxygraph system and rat C6, stable C6 transformant cells overexpressing mouse DAO (designated as C6/DAO) and pig kidney epithelial cells (LLC-PK(1)). Risperidone has a hyperbolic mixed-type inhibition, designated as 'partial uncompetitive inhibition effect', with K(i) value of 41 microM on human DAO. Risperidone exhibited a protective effect from D-amino acid induced cell death in both C6/DAO and LLC-PK(1) cells with 10% increase in viability. These data indicate the involvement of DAO activity in D-serine metabolism and also suggest a new mechanism of action to risperidone as antischizophrenic drug.
authors.affiliation: Division of Enzyme Pathophysiology, The Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
authors.forename: R M
authors.initials: RM
authors.lastname: Abou El-Magd
authors.forename: H K
authors.initials: HK
authors.lastname: Park
authors.forename: T
authors.initials: T
authors.lastname: Kawazoe
authors.forename: S
authors.initials: S
authors.lastname: Iwana
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: S P
authors.initials: SP
authors.lastname: Chung
authors.forename: M
authors.initials: M
authors.lastname: Miyano
authors.forename: K
authors.initials: K
authors.lastname: Yorita
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Fukui