Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia

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 gen...

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Veröffentlicht in:European journal of pharmacology 2022-09, Vol.931, p.175207-175207, Article 175207
Hauptverfasser: Takase, Saeko, Liao, Jingzhu, Liu, Yue, Tanaka, Rinako, Miyagawa, Yasuhiro, Sawahata, Masahito, Sobue, Akira, Mizoguchi, Hiroyuki, Nagai, Taku, Kaibuchi, Kozo, Ozaki, Norio, Yamada, Kiyofumi
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container_title European journal of pharmacology
container_volume 931
creator Takase, Saeko
Liao, Jingzhu
Liu, Yue
Tanaka, Rinako
Miyagawa, Yasuhiro
Sawahata, Masahito
Sobue, Akira
Mizoguchi, Hiroyuki
Nagai, Taku
Kaibuchi, Kozo
Ozaki, Norio
Yamada, Kiyofumi
description 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 Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 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 Ki 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. [Display omitted] •Fasudil and hydroxyfasudil concentrations reached Ki values for Rho-kinase with fasudil (10 mg kg−1, i.p.).•Fasudil improved MK-801-induced deficits in locomotion, social behavior, prepulse inhibition and novel object recognition.•Fasudil may have antipsychotic-like effects comparable to haloperidol and clozapine in schizophrenia.
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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 Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 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 Ki 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. 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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 Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 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 Ki 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. [Display omitted] •Fasudil and hydroxyfasudil concentrations reached Ki values for Rho-kinase with fasudil (10 mg kg−1, i.p.).•Fasudil improved MK-801-induced deficits in locomotion, social behavior, prepulse inhibition and novel object recognition.•Fasudil may have antipsychotic-like effects comparable to haloperidol and clozapine in schizophrenia.</description><subject>Behavioral test</subject><subject>Fasudil</subject><subject>MK-801</subject><subject>Schizophrenia</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kM1LxDAQxYMouH78Bx569GDXSTZtk4sg4hcIgug5pOnEztptatIV9K-3Sz17moF57w3vx9gZhyUHXl6ul7geWhuXAoRY8qoQUO2xBVeVzqHiYp8tALjMhdb6kB2ltAaAQotiwcJ1P9KQvl0bRnJ5Rx-YoffoxpQFn3mbtg11F5nNXtqQf1BvE2bUt1TTGOLFtE6n3e-NdaEL7-Qy29PGdtkmNNjtMpJr6ScMbcSe7Ak78LZLePo3j9nb3e3rzUP-9Hz_eHP9lDsJxZiXokSvi6bGVaOVrlfC-dpLLZSsSysVbzgicqcKt2qkdAIrULW3XEtQZQGrY3Y-5w4xfG4xjWZDyWHX2R7DNhlRgVSlBiUnqZylLoaUInozxKlB_DYczI6vWZuZr9nxNTPfyXY123Cq8UUYTXKEvcOG4oTPNIH-D_gFviaG8A</recordid><startdate>20220915</startdate><enddate>20220915</enddate><creator>Takase, Saeko</creator><creator>Liao, Jingzhu</creator><creator>Liu, Yue</creator><creator>Tanaka, Rinako</creator><creator>Miyagawa, Yasuhiro</creator><creator>Sawahata, Masahito</creator><creator>Sobue, Akira</creator><creator>Mizoguchi, Hiroyuki</creator><creator>Nagai, Taku</creator><creator>Kaibuchi, Kozo</creator><creator>Ozaki, Norio</creator><creator>Yamada, Kiyofumi</creator><general>Elsevier B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20220915</creationdate><title>Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia</title><author>Takase, Saeko ; Liao, Jingzhu ; Liu, Yue ; Tanaka, Rinako ; Miyagawa, Yasuhiro ; Sawahata, Masahito ; Sobue, Akira ; Mizoguchi, Hiroyuki ; Nagai, Taku ; Kaibuchi, Kozo ; Ozaki, Norio ; Yamada, Kiyofumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-626ef95dbe3d989b32cfbf49284b6a481d1eee1c85c3d44c2e708bfa194086503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Behavioral test</topic><topic>Fasudil</topic><topic>MK-801</topic><topic>Schizophrenia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takase, Saeko</creatorcontrib><creatorcontrib>Liao, Jingzhu</creatorcontrib><creatorcontrib>Liu, Yue</creatorcontrib><creatorcontrib>Tanaka, Rinako</creatorcontrib><creatorcontrib>Miyagawa, Yasuhiro</creatorcontrib><creatorcontrib>Sawahata, Masahito</creatorcontrib><creatorcontrib>Sobue, Akira</creatorcontrib><creatorcontrib>Mizoguchi, Hiroyuki</creatorcontrib><creatorcontrib>Nagai, Taku</creatorcontrib><creatorcontrib>Kaibuchi, Kozo</creatorcontrib><creatorcontrib>Ozaki, Norio</creatorcontrib><creatorcontrib>Yamada, Kiyofumi</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takase, Saeko</au><au>Liao, Jingzhu</au><au>Liu, Yue</au><au>Tanaka, Rinako</au><au>Miyagawa, Yasuhiro</au><au>Sawahata, Masahito</au><au>Sobue, Akira</au><au>Mizoguchi, Hiroyuki</au><au>Nagai, Taku</au><au>Kaibuchi, Kozo</au><au>Ozaki, Norio</au><au>Yamada, Kiyofumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia</atitle><jtitle>European journal of pharmacology</jtitle><date>2022-09-15</date><risdate>2022</risdate><volume>931</volume><spage>175207</spage><epage>175207</epage><pages>175207-175207</pages><artnum>175207</artnum><issn>0014-2999</issn><eissn>1879-0712</eissn><abstract>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 Ki values for Rho-kinase after intraperitoneal injection of 10 mg kg−1 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 Ki 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. [Display omitted] •Fasudil and hydroxyfasudil concentrations reached Ki values for Rho-kinase with fasudil (10 mg kg−1, i.p.).•Fasudil improved MK-801-induced deficits in locomotion, social behavior, prepulse inhibition and novel object recognition.•Fasudil may have antipsychotic-like effects comparable to haloperidol and clozapine in schizophrenia.</abstract><pub>Elsevier B.V</pub><doi>10.1016/j.ejphar.2022.175207</doi><tpages>1</tpages></addata></record>
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subjects Behavioral test
Fasudil
MK-801
Schizophrenia
title Antipsychotic-like effects of fasudil, a Rho-kinase inhibitor, in a pharmacologic animal model of schizophrenia
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