Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia.
Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia.
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法舒地尔（一种 Rho 激酶抑制剂）在精神分裂症药理动物模型中的抗精神病样作用。
DOI：
10.1016/j.ejphar.2022.175207
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发表时间：
2022
影响因子：
5
通讯作者：
Yamada K.
中科院分区：
文献类型：
--
作者：
Takase S;Liao J;Liu Y;Tanaka R;Miyagawa Y;Sawahata M;Sobue A;Mizoguchi H;Nagai T;Kaibuchi K;Ozaki N;Yamada K.
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阻力。我们最近利用全基因组分析发现精神分裂症与Rho GTPase激活蛋白10(ARHGAP10)基因的外显子拷贝数变异显著相关。ARHGAP10编码一个参与小GTPase信号转导的RhoGAP超家族成员。在小鼠中，Arhgap10基因变异导致RhoA/Rho-Kinase途径激活。用高效液相色谱-串联质谱法研究了法舒地尔和羟基法舒地尔在小鼠体内的药代动力学。在MK-801药物治疗的小鼠精神分裂症模型中，还研究了法舒地尔对多动、社会互动缺陷、脉搏前抑制缺陷和新的物体识别缺陷的抗精神病作用。腹腔注射−-1法舒地尔10 mg/kg后，在脑内检测到Rho-K的浓度高于其各自的Ki值。法舒地尔以剂量依赖的方式改善MK-801处理的小鼠的多动、社会互动缺陷、脉冲前抑制缺陷和新的目标识别缺陷。口服法舒地尔后，脑组织中的羟基法舒地尔浓度高于Rho-Kinase的KiValue，而法舒地尔则未被检测到。口服法舒地尔也能改善MK-801诱导的多动反应。这些结果表明，法舒地尔对MK-801治疗的药理小鼠精神分裂症模型具有抗精神病药样作用。Rho-Kinase有两种亚型，在MK-801治疗的小鼠精神分裂症模型中，法舒地尔的抗精神病药样作用涉及到两种亚型，还需要进一步的研究。
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.ARHGAP10encodes a RhoGAP superfamily member that is involved in small GTPase signaling. In mice,Arhgap10gene 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 respectiveKivalues for Rho-kinase after intraperitoneal injection of 10 mg kg−1fasudil. 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 theKivalue 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.
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