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

Takase, Saeko; Liao, Jingzhu; Liu, Yue; Tanaka, Rinako; Miyagawa, Yasuhiro; Sawahata, Masahito; Sobue, Akira; Mizoguchi, Hideaki; Nagai, Taku; Kaibuchi, Kozo; Ozaki, Norio; Yamada, Kiyofumi

doi:10.1016/j.ejphar.2022.175207

Cited by 12 publications

(9 citation statements)

References 43 publications

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“…We have shown that fasudil ameliorates cognitive impairment in a mouse model of SCZ induced by MK-801 treatment (Takase et al, 2022). The fact that fasudil did not influence METH-induced hyperactivity in mice might indicate that the effect of fasudil in patients with SCZ may be limited to cognitive deficits and that Rho kinase inhibitors may have a minimal impact on positive symptoms such as hallucinations and delusions.…”

Section: Discussionmentioning

confidence: 89%

“…We have previously demonstrated that plasma and brain concentrations of fasudil and its active metabolite hydroxyfasudil increase in a dose-dependent manner in mice after i.p. injection of fasudil, and that fasudil at 10 mg/kg inhibits Rho-kinase activity in mouse brain for at least 60 min (Takase et al, 2022). The i.p.…”

Section: Resultsmentioning

confidence: 99%

“…Based on our previous pharmacokinetic study of fasudil in mice that used liquid chromatography-tandem mass spectrometry analysis to determine the plasma and brain levels of fasudil and its active metabolite, hydroxyfasudil (Takase et al, 2022), fasudil (10 or 20 mg/kg) was administered i.p. 5 min before or orally (p.o.)…”

Section: Drug Treatment Schedulementioning

confidence: 99%

“…The dose of fasudil (20 mg/kg, p.o.) was selected based on our previous pharmacokinetic study in mice (Takase et al, 2022). The brain levels of fasudil and hydroxyfasudil 20 min after oral administration of fasudil at 20 mg/kg were 118 ± 45 ng/g and 164 ± 25 ng/g tissue, respectively (n = 3).…”

Section: Intraperitoneal Administration Of Fasudil Ameliorates Meth-i...mentioning

confidence: 99%

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Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

Liao

Wulaer

Mizoguchi

et al. 2022

Preprint

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Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Although its pathoetiology remains unclear, it is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)–treated mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced impairment of VD. Fasudil also significantly suppressed the increase in the number of c-Fos–positive cells in the medial prefrontal cortex (mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, the other Rho kinase inhibitor, into the mPFC or DMS significantly ameliorated the METH-induced impairment of VD. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Both haloperidol and fasudil ameliorated the METH-induced impairment of VD, while clozapine had little effect. Both haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. Finally, haloperidol and clozapine significantly suppressed the METH-induced increase in MYPT1 (Thr696) phosphorylation in the mPFC, but not in the DMS. Thus, the METH-induced cognitive function impairment was ameliorated by treatment with Rho kinase inhibitors, which may act via the cortico-striatal circuit.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Drug Treatment Schedulementioning

confidence: 99%

Section: Intraperitoneal Administration Of Fasudil Ameliorates Meth-i...mentioning

confidence: 99%

See 2 more Smart Citations

Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

Liao

Wulaer

Mizoguchi

et al. 2022

Preprint

Self Cite

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“…First, the selection method of peptides in this study was relatively simple, but a previous study indicated that the neurological symptoms caused by COVID-19 are diverse ( Zhang et al, 2021 ). The PPI test used in the selection is commonly regarded as an operational assessment of sensorimotor gating ( Takase et al, 2022 ), which only examines the behavioral change from one dimension. As a result, we might have missed several potentially harmful non-neutralizing antibodies that lead to other symptoms.…”

Section: Discussionmentioning

confidence: 99%

Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice

Wei

You

et al. 2023

Front. Mol. Neurosci.

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ObjectiveAn increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS.MethodsAfter 14-day acclimation, the grouped ApoE-/- mice were immunized four times (day 0, day 7, day 14, day 28) with different spike-protein-derived peptides (coupled with KLH) or KLH via subcutaneous injection. Antibody level, state of glial cells, gene expression, prepulse inhibition, locomotor activity, and spatial working memory were assessed from day 21.ResultsAn increased level of anti-S1-111 IgG was measured in their sera and brain homogenate after the immunization. Crucially, anti-S1-111 IgG increased the density of microglia, activated microglia, and astrocytes in the hippocampus, and we observed a psychomotor-like behavioral phenotype with defective sensorimotor gating and impaired spontaneity among S1-111-immunized mice. Transcriptome profiling showed that up-regulated genes in S1-111-immunized mice were mainly associated with synaptic plasticity and mental disorders.DiscussionOur results show that the non-neutralizing antibody anti-S1-111 IgG induced by the spike protein caused a series of psychotic-like changes in model mice by activating glial cells and modulating synaptic plasticity. Preventing the production of anti-S1-111 IgG (or other non-neutralizing antibodies) may be a potential strategy to reduce CNS manifestations in COVID-19 patients and vaccinated individuals.

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Current development in sulfonamide derivatives to enable CNS-drug discovery

Blicharz-Futera,

Kamiński,

Grychowska

et al. 2024

Bioorganic Chemistry

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

Cited by 12 publications

References 43 publications

Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

Rho kinase inhibitors ameliorate acute methamphetamine-induced cognitive impairment through the cortico-striatal circuit in mice

Non-neutralizing antibodies to SARS-Cov-2-related linear epitopes induce psychotic-like behavior in mice

Current development in sulfonamide derivatives to enable CNS-drug discovery

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