D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog.
D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog.
复制标题
D-氨基酸氧化酶抑制会增加小鼠的 D-丝氨酸血浆水平，但不会增加猴子或狗的血浆水平。
DOI：
10.1038/npp.2015.319
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Slusher,BarbaraS
中科院分区：
文献类型：
--
作者：
Rojas,Camilo;Alt,Jesse;Ator,NancyA;Thomas,AjitG;Wu,Ying;Hin,Niyada;Wozniak,Krystyna;Ferraris,Dana;Rais,Rana;Tsukamoto,Takashi;Slusher,BarbaraS
D-丝氨酸已被证明在用作治疗精神分裂症的附加疗法时可改善阳性、阴性和认知症状。然而，D-丝氨酸必须以高剂量施用以观察临床效果。这被认为是由于D-丝氨酸在到达大脑之前经历了D-氨基酸氧化酶（DAAO）的氧化。因此，D-丝氨酸与DAAO抑制剂的联合给药可能是降低治疗精神分裂症所需的D-丝氨酸剂量的一种方法。在啮齿动物中评估该假设的早期研究表明，与单独施用D-丝氨酸相比，结构不同的DAAO抑制剂与D-丝氨酸的伴随施用增强了啮齿动物中的血浆和脑D-丝氨酸水平。在目前的工作中，我们使用了三种有效的DAAO抑制剂，并证实了先前在小鼠中的结果。在后续工作中，我们评估了在存在或不存在这些DAAO抑制剂的情况下口服D-丝氨酸后猴子的血浆D-丝氨酸水平。即使化合物达到超过其Ki值> 60倍的稳态血浆浓度，血浆D-丝氨酸水平仍保持与不存在DAAO抑制剂时的水平相同。在狗身上也得到了类似的结果。总之，与啮齿类动物相比，猴和犬中的DAAO抑制不影响外源性D-丝氨酸给药的暴露量。结果可能是由于D-丝氨酸代谢和/或清除机制的差异，并表明DAAO在D-丝氨酸代谢中的作用在不同物种之间是不同的。这些数据提供了关于DAAO抑制对精神分裂症患者的效用的警告。
D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to D-serine undergoing oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine with a DAAO inhibitor could be a way to lower the D-serine dose required to treat schizophrenia. Early studies in rodents to evaluate this hypothesis showed that concomitant administration of structurally distinct DAAO inhibitors with D-serine enhanced plasma and brain D-serine levels in rodents compared with administration of D-serine alone. In the present work we used three potent DAAO inhibitors and confirmed previous results in mice. In a follow-up effort, we evaluated plasma D-serine levels in monkeys after oral administration of D-serine in the presence or absence of these DAAO inhibitors. Even though the compounds reached steady state plasma concentrations exceeding their K i values by> 60-fold, plasma D-serine levels remained the same as those in the absence of DAAO inhibitors. Similar results were obtained with dogs. In summary, in contrast to rodents, DAAO inhibition in monkeys and dogs did not influence the exposure to exogenously administered D-serine. Results could be due to differences in D-serine metabolism and/or clearance mechanisms and suggest that the role of DAAO in the metabolism of D-serine is different across species. These data provide caution regarding the utility of DAAO inhibition for patients with schizophrenia.