The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia

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-PK1). Risperidone has a hyperbolic mixed- type inhibition, designated as 'partial uncompetitive inhibition effect', with K-i value of 41 mu M on human DAO. Risperidone exhibited a protective effect from D-amino acid induced cell death in both C6/DAO and LLC-PK1 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.

D - 氨基酸氧化酶（DAO）已被确定参与D - 丝氨酸的氧化过程，D - 丝氨酸是大脑中N - 甲基 - D - 天冬氨酸型谷氨酸受体的变构激活剂，并且与精神分裂症的发病有关。使用体外测氧系统以及大鼠C6细胞、过表达小鼠DAO的稳定C6转化细胞（命名为C6/DAO）和猪肾上皮细胞（LLC - PK1），对利培酮（一种苯并异恶唑衍生物，非典型抗精神分裂症药物）对人DAO活性的影响进行了测试。利培酮具有双曲线混合型抑制作用，被称为“部分非竞争性抑制效应”，对人DAO的Ki值为41μM。利培酮在C6/DAO和LLC - PK1细胞中均表现出对D - 氨基酸诱导的细胞死亡的保护作用，细胞活力提高了10%。这些数据表明DAO活性参与D - 丝氨酸代谢，也提示了利培酮作为抗精神分裂症药物的一种新作用机制。