Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan; Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama, 930-0194, Japan.
Eur J Pharmacol. 2022 Sep 15;931:175207. doi: 10.1016/j.ejphar.2022.175207. Epub 2022 Aug 18.
Current antipsychotics used to treat schizophrenia have associated problems, including serious side effects and treatment resistance. We recently identified a significant association of schizophrenia with exonic copy number variations in the Rho GTPase activating protein 10 (ARHGAP10) gene using genome-wide analysis. ARHGAP10 encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice, Arhgap10 gene variations result in RhoA/Rho-kinase pathway activation. We evaluated the pharmacokinetics of fasudil and hydroxyfasudil using liquid chromatography-tandem mass spectrometry in mice. The antipsychotic effects of fasudil on hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits were also investigated in a MK-801-treated pharmacological mouse schizophrenia model. Fasudil and its major metabolite, hydroxyfasudil, were detected in the brain at concentrations above their respective K values for Rho-kinase after intraperitoneal injection of 10 mg kg fasudil. Fasudil improved the hyperlocomotion, social interaction deficits, prepulse inhibition deficits, and novel object recognition deficits in MK-801-treated mice in a dose-dependent manner. Following oral administration of fasudil, brain hydroxyfasudil was detected at concentration above the K value for Rho-kinase whilst fasudil was undetectable. MK-801-induced hyperlocomotion was also improved by oral fasudil administration. These results suggest that fasudil has antipsychotic-like effects on the MK-801-treated pharmacological mouse schizophrenia model. There are two isoforms in Rho-kinase, and further investigation is needed to clarify the isoforms involved in the antipsychotic-like effects of fasudil in the MK-801-treated mouse schizophrenia model.
目前用于治疗精神分裂症的抗精神病药物存在相关问题，包括严重的副作用和治疗抵抗。我们最近使用全基因组分析发现， Rho GTPase 激活蛋白 10（ARHGAP10）基因的外显子拷贝数变异与精神分裂症显著相关。ARHGAP10 编码一种 RhoGAP 超家族成员，参与小 GTPase 信号转导。在小鼠中，Arhgap10 基因变异导致 RhoA/Rho-kinase 途径激活。我们使用液相色谱-串联质谱法在小鼠中评估了法舒地尔和羟基法舒地尔的药代动力学。还在 MK-801 处理的药理学小鼠精神分裂症模型中研究了法舒地尔对过度活跃、社交互动缺陷、预脉冲抑制缺陷和新物体识别缺陷的抗精神病作用。腹腔注射 10mg/kg 法舒地尔后，法舒地尔及其主要代谢物羟基法舒地尔在大脑中的浓度高于各自对 Rho-kinase 的 K 值，均可被检测到。法舒地尔以剂量依赖性方式改善了 MK-801 处理的小鼠的过度活跃、社交互动缺陷、预脉冲抑制缺陷和新物体识别缺陷。口服法舒地尔后，大脑中的羟基法舒地尔浓度高于 Rho-kinase 的 K 值，而法舒地尔无法检测到。MK-801 诱导的过度活跃也被口服法舒地尔改善。这些结果表明，法舒地尔对 MK-801 处理的药理学小鼠精神分裂症模型具有抗精神病样作用。Rho-kinase 有两种同工型，需要进一步研究以阐明参与法舒地尔在 MK-801 处理的小鼠精神分裂症模型中的抗精神病样作用的同工型。
