Faculty Profiles - MIZOGUCHI, Hiroyuki

Papers - MIZOGUCHI, Hiroyuki

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Population pharmacokinetic model of tranexamic acid in patients who undergo cardiac surgery with cardiopulmonary bypass Open Access

Nakai, T; Tamura, T; Miyagawa, Y; Inagaki, T; Mutsuga, M; Yamada, S; Yamada, K; Nishiwaki, K; Mizoguchi, H

EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY Vol. 81 ( 3 ) page： 441 - 449 2025.3

Language：English Publisher：European Journal of Clinical Pharmacology

Purpose: Tranexamic acid (TXA) is widely used as an antifibrinolytic drug. However, studies to determine the optimal blood concentration of TXA have produced inconsistent results. During cardiac surgery, cardiopulmonary bypass (CPB) has serious effects on drug distribution, elimination, and plasma concentration. Therefore, we aimed to establish a population pharmacokinetics model of TXA in patients undergoing cardiac surgery with CPB that considers renal function as a covariate, thereby facilitating personalized treatment. Methods: In total, 453 TXA plasma samples were prospectively collected from 77 patients who underwent cardiac surgery with CPB. Plasma concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model of TXA was analyzed using nonlinear mixed-effects modeling. Results: The two-compartment–based model with combined errors was determined as the best. The final model included the effect of bodyweight and CLcr may be summarized as V1 (L) = 12.77 × (bodyweight / 61.4)0.911, V2 (L) = 6.857, CL1 (L/h) = 3.263 × [CLcr (L/h) / 61.0]0.752, CL2 (L/h) = 2.859. Conclusion: Patients who undergo cardiac surgery with CPB may require an adjusted dose of TXA tailored to CPB due to lower CL1 and increased V1. Our TXA population pharmacokinetic model may be useful for developing individualized dosing designs for TXA in patients who undergo cardiac surgery with CPB.

DOI： 10.1007/s00228-025-03802-0

GLIA RESPONSES ARE ASSOCIATED WITH ABNORMAL BEHAVIORS IN AN ANIMAL MODEL OF TAU PATHOLOGIES

Liu, Y; Mizoguchi, H; Sobue, A; Sahara, N; Yamanaka, K; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 28 2025.2

A RHO-KINASE 2 SELECTIVE INHIBITOR KD025 AMELIORATES SCHIZOPHRENIA-LIKE BEHAVIORS IN MK-801-TREATED MICE

Tanaka, R; Liu, Y; Liao, JZ; Mouri, A; Nagai, T; Nabeshima, T; Kaibuchi, K; Tachibana, D; Kobayashi, Y; Ozaki, N; Mizoguchi, H; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 28 page： i51 - i52 2025.2

ACTIVITIES OF OREXIN NEURONS IN MOTIVATIVE BEHAVIOR

Mizoguchi, H; Dong, YT; Yamanaka, A; Yamada, K

INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 28 page： I24 - I25 2025.2

Effects of Drug-related Problem Interventions by Hospital Pharmacists in Patients with Mild-to-moderate COVID-19

Fukuzawa Shota, Miyagawa Yasuhiro, Kawarada Yuki, Matsunaga Ami, Toma Nika, Saeki Yuri, Mizoguchi Hiroyuki, Yamada Kiyofumi

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) Vol. 50 ( 11 ) page： 614 - 621 2024.11

Language：Japanese Publisher：Japanese Society of Pharmaceutical Health Care and Sciences

COVID-19 has been downgraded from a Class 2 disease to a Class 5 disease under the Infectious Disease Control Law in Japan on May 8, 2023. Previously, patients with COVID-19 were treated in specialized isolation wards. Patients with mild-to-moderate COVID-19 are now being treated in general wards, similar to seasonal influenza. Thus, more clinical pharmacists should be involved in COVID-19 patient care. Although the effects of pharmacological interventions for severe COVID-19 have been reported, they have not been reported for mild-to-moderate COVID-19. In this study, we evaluated the effects of pharmacological interventions for drug-related problems (DRPs) in patients with mild-to-moderate COVID-19 symptoms. We investigated patients hospitalized in isolation wards exclusively for COVID-19 from January 2022 to March 2023 at our institution. Among the 393 patients enrolled, 271 DRPs were identified by clinical pharmacists. There were 48 and 223 DRPs related to COVID-19 treatment and other factors, respectively. Clinical pharmacists provided 271 interventions on DRPs, of which 247 (91.1％) were accepted by the prescriber. These results indicate that patients with mild-to-moderate COVID-19 frequently receive DRPs, and clinical pharmacist interventions have positive effects on COVID-19 treatment and medication safety.

DOI： 10.5649/jjphcs.50.614

CiNii Research

The Use of Text Mining to Obtain a Historical Overview of Research on Therapeutic Drug Monitoring Open Access

Matsuzaki Tetsuo, Mizoguchi Hiroyuki, Yamada Kiyofumi

Biological and Pharmaceutical Bulletin Vol. 47 ( 11 ) page： 1883 - 1892 2024.11

Language：English Publisher：The Pharmaceutical Society of Japan

Therapeutic drug monitoring (TDM) is a routine clinical practice used to individualize drug dosing to maintain drug efficacy and minimize the consequences of overexposure. TDM is applied to many drug classes, including immunosuppressants, antineoplastic agents, and antibiotics. Considerable effort has been made to establish routine TDM practices for each drug. However, because TDM has been developed within the context of specific drugs, there is insufficient understanding of historical trends within the field of TDM research as a whole. In this study, we employed text-mining approaches to explore trends in the TDM research field. We first performed a PubMed search to determine which drugs and drug classes have been extensively studied in the context of TDM. This investigation revealed that the most commonly studied drugs are tacrolimus, followed by cyclosporine and vancomycin. With regard to drug classes, most studies focused on immunosuppressants, antibiotics, and antineoplastic agents. We also subjected PubMed records of TDM-related studies to a series of text-mining pipelines. Our analyses revealed how TDM research has evolved over the years, thereby serving as a cornerstone for forecasting future research trends.

DOI： 10.1248/bpb.b24-00319

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature Open Access

Mori, D; Inami, C; Ikeda, R; Sawahata, M; Urata, S; Yamaguchi, ST; Kobayashi, Y; Fujita, K; Arioka, Y; Okumura, H; Kushima, I; Kodama, A; Suzuki, T; Hirao, T; Yoshimi, A; Sobue, A; Ito, T; Noda, Y; Mizoguchi, H; Nagai, T; Kaibuchi, K; Okabe, S; Nishiguchi, K; Kume, K; Yamada, K; Ozaki, N

TRANSLATIONAL PSYCHIATRY Vol. 14 ( 1 ) page： 216 2024.5

Language：English Publisher：Translational Psychiatry

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

DOI： 10.1038/s41398-024-02952-6

Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice Open Access

Mori, D; Ikeda, R; Sawahata, M; Yamaguchi, S; Kodama, A; Hirao, T; Arioka, Y; Okumura, H; Inami, C; Suzuki, T; Hayashi, Y; Kato, H; Nawa, Y; Miyata, S; Kimura, H; Kushima, I; Aleksic, B; Mizoguchi, H; Nagai, T; Nakazawa, T; Hashimoto, R; Kaibuchi, K; Kume, K; Yamada, K; Ozaki, N

TRANSLATIONAL PSYCHIATRY Vol. 14 ( 1 ) page： 138 2024.3

Language：English Publisher：Translational Psychiatry

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

DOI： 10.1038/s41398-023-02679-w

Orexinergic neurons contribute to autonomic cardiovascular regulation for locomotor exercise Open Access

Narai, E; Yoshimura, Y; Honaga, T; Mizoguchi, H; Yamanaka, A; Hiyama, TY; Watanabe, T; Koba, S

JOURNAL OF PHYSIOLOGY-LONDON 2024.2

Language：English Publisher：Journal of Physiology

Abstract: While the hypothalamic orexinergic nervous system is established as having a pivotal role in the long-term regulation of various organismic functions, including wakefulness, metabolism and hypertensive states, whether this system contributes to the rapid autonomic cardiovascular regulation during physical activity remains elusive. This study aimed to elucidate the role of the orexinergic nervous system in transmitting volitional motor signals, i.e. central command, to drive somatomotor and sympathetic cardiovascular responses. We first found that this system is activated by voluntary locomotor exercise as evidenced by an increased expression of Fos, a marker of neural activation, in the orexinergic neurons of Sprague–Dawley rats engaged in spontaneous wheel running. Next, using transgenic Orexin-Cre rats for optogenetic manipulation of orexinergic neurons, we found that optogenetic excitation of orexinergic neurons caused sympathoexcitation on a subsecond timescale under anaesthesia. In freely moving conscious rats, this excitatory stimulation rapidly elicited exploration-like behaviours, predominantly locomotor activity, along with pressor and tachycardiac responses. Meanwhile, optogenetic inhibition of orexinergic neurons during spontaneous wheel running immediately suppressed locomotor activities and blood pressure elevation without affecting basal cardiovascular homeostasis. Taken together, these findings demonstrate the essential role of the orexinergic nervous system in the central circuitry that transmits central command signals for locomotor exercise. This study not only offers insights into the brain circuit mechanisms precisely regulating autonomic cardiovascular systems during voluntary exercise but also likely contributes to our understanding of brain mechanisms underlying abnormal cardiovascular adjustments to exercise in pathological conditions, such as hypertension. (Figure presented.). Key points: The hypothalamic orexinergic nervous system plays various roles in the long-term regulation of autonomic and endocrine functions, as well as motivated behaviours. We present a novel, rapid role of the orexinergic nervous system, revealing its significance as a crucial substrate in the brain circuit mechanisms that coordinate somatomotor and autonomic cardiovascular controls for locomotor exercise. Our data demonstrate that orexinergic neurons relay volitional motor signals, playing a necessary and sufficient role in the autonomic cardiovascular regulation required for locomotor exercise in rats. The findings contribute to our understanding of how the brain precisely regulates autonomic cardiovascular systems during voluntary exercise, providing insights into the central neural mechanisms that enhance physical performance moment-by-moment during exercise.

DOI： 10.1113/JP285791

Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia Open Access

Liao, JZ; Dong, GY; Zhu, WJ; Wulaer, B; Mizoguchi, H; Sawahata, M; Liu, Y; Kaibuchi, K; Ozaki, N; Nabeshima, T; Nagai, T; Yamada, K

PHARMACOLOGICAL RESEARCH Vol. 194 page： 106838 2023.8

Language：English Publisher：Pharmacological Research

Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic treatment in SCZ improves positive symptoms but has major side effects and little impact on negative symptoms and cognitive impairment. The pathoetiology of SCZ remains unclear, but 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 male mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced VD impairment. Fasudil also significantly suppressed the increase in the number of c-Fos–positive cells in the infralimbic medial prefrontal cortex (infralimbic mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, another Rho kinase inhibitor, into the infralimbic mPFC or DMS significantly ameliorated METH-induced VD impairment. 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 infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Oral administration of haloperidol and fasudil ameliorated METH-induced VD impairment, while clozapine had little effect. Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit.

DOI： 10.1016/j.phrs.2023.106838

Fasudil ameliorates methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated gene mutations in the Arhgap10 gene

Tanaka, R; Liao, JZ; Mori, D; Nagai, T; Matsuzaki, T; Nabeshima, T; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Yamada, K

BRITISH JOURNAL OF PHARMACOLOGY Vol. 180 page： 1004 - 1004 2023.7

Retrospective Analysis of Neutrophil-to-Lymphocyte Ratio in Patients with Melanoma Who Received Ipilimumab Monotherapy or Ipilimumab in Combination with Nivolumab in Japan Open Access

Matsumura Yuka, Kawarada Yuki, Matsuo Momo, Yokota Kenji, Mizoguchi Hiroyuki, Akiyama Masashi, Yamada Kiyofumi

Biological and Pharmaceutical Bulletin Vol. 46 ( 3 ) page： 427 - 431 2023.3

Language：English Publisher：The Pharmaceutical Society of Japan

Studies have reported an association between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis in patients with melanoma treated with ipilimumab. However, it remains unclear whether NLR is useful in Japanese patients with melanoma, and if so, what is the optimal cut-off value. We retrospectively examined 38 patients who received ipilimumab from August 2015 to November 2021 at Nagoya University Hospital. We divided patients into two groups: 1–2 versus 3–4 cycles of ipilimumab. In univariate analysis, baseline neutrophil count and NLR were significantly higher in patients who discontinued ipilimumab within 2 cycles. With receiver operating characteristic analysis, the optimal NLR cut-off value was found to be 3.4 (area under the curve, 0.75; 95% confidence interval, 0.58–0.92). In multivariate logistic regression analysis, baseline NLR >3.4 was an independent risk factor for ipilimumab discontinuation (odds ratio, 15.6; 95% confidence interval, 3.0–82) that was significantly associated with shorter progression-free survival (PFS) (p = 0.003, log-rank test). In conclusion, NLR >3.4 is useful for selecting Japanese patients with melanoma who might have better PFS with ipilimumab-containing treatment. Because the optimal NLR cut-off value in this study was lower than values in American and European studies, it possibly differs by race. Hence, it should be extrapolated to Japanese patients with caution.

DOI： 10.1248/bpb.b22-00750

Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene Reviewed Open Access

Tanaka, R; Liao, JZ; Hada, K; Mori, D; Nagai, T; Matsuzaki, T; Nabeshima, T; Kaibuchi, K; Ozaki, N; Mizoguchi, H; Yamada, K

PHARMACOLOGICAL RESEARCH Vol. 187 page： 106589 2023.1

Language：English Publisher：Pharmacological Research

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase–activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry “double-hit” mutations in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen‑based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase–targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC. Moreover, fasudil (3–20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

DOI： 10.1016/j.phrs.2022.106589

Abnormal behavior and glial responses in an animal model of tau pathology

Liu Yue, Mizoguchi Hiroyuki, Sobue Akira, Shara Naruhiko, Yamanaka Koji, Yamada Kiyofumi

Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. 97 ( 0 ) page： 2-B-P-037 2023

Language：Japanese Publisher：Japanese Pharmacological Society

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease and related tauopathies and has gained prominence in the development of therapies for Alzheimer’s disease. Neuroinflammation plays an important role in the progression of neurodegenerative disorders, and activated astrocytes and microglia strongly influence Aβ and tau pathologies. Numerous transgenic mouse models that recapitulate critical Alzheimer’s disease-like pathology have been developed to examine the pathogenic mechanisms underlying Alzheimer’s disease and evaluate therapeutic approaches targeting tau, but the relevant mechanisms remain unknown. In this study, we investigated changes in gene expression related to neuroinflammation in glial cells of rTg4510 mice, an animal model of non-Alzheimer’s disease tauopathy. First, we analyzed 4- and 6-month-old rTg4510 mice in terms of cognition and behaviors that mimic the behavioral and psychological problems of dementia. Deterioration of executive functions and impairment of daily life activities are early signs of Alzheimer’s disease. In the present study, nest-building behavior, which represents active interaction with the environment, evaluated the executive functions that are the basis of daily life activities. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nesting behavior compared with control mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a greater amount of time in the open arm of the plus-maze test than control mice. We also used magnetic-activated cell sorting to analyze the expressions of genes related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Axl, Cd11c, and CD68 expression levels were increased in microglial cells, and H2-D1, Psmb8, and H2-T23 expression levels in astrocytes were also increased in 6-month-old rTg4510 mice compared with control mice. In conclusion, neuroinflammation may be related to neuronal degeneration and abnormal behavior in rTg4510 mice.

DOI： 10.1254/jpssuppl.97.0_2-b-p-037

CiNii Research

Nanobody-based RFP-dependent Cre recombinase for selective anterograde tracing in RFP-expressing transgenic animals Reviewed Open Access

Inutsuka, A; Maejima, S; Mizoguchi, H; Kaneko, R; Nomura, R; Takanami, K; Sakamoto, H; Onaka, T

COMMUNICATIONS BIOLOGY Vol. 5 ( 1 ) page： 979 2022.9

Language：English Publisher：Communications Biology

Transgenic animals expressing fluorescent proteins are widely used to label specific cells and proteins. By using a split Cre recombinase fused with mCherry-binding nanobodies or designed ankyrin repeat proteins, we created Cre recombinase dependent on red fluorescent protein (RFP) (Cre-DOR). Functional binding units for monomeric RFPs are different from those for polymeric RFPs. We confirmed selective target RFP-dependent gene expression in the mouse cerebral cortex using stereotaxic injection of adeno-associated virus vectors. In estrogen receptor-beta (Esr2)-mRFP1 mice and gastrin-releasing peptide receptor (Grpr)-mRFP1 rats, we confirmed that Cre-DOR can be used for selective tracing of the neural projection from RFP-expressing specific neurons. Cellular localization of RFPs affects recombination efficiency of Cre-DOR, and light and chemical-induced nuclear translocation of an RFP-fused protein can modulate Cre-DOR efficiency. Our results provide a method for manipulating gene expression in specific cells expressing RFPs and expand the repertory of nanobody-based genetic tools.

DOI： 10.1038/s42003-022-03944-2

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

Takase, S; Liao, JZ; Liu, Y; Tanaka, R; Miyagawa, Y; Sawahata, M; Sobue, A; Mizoguchi, H; Nagai, T; Kaibuchi, K; Ozaki, N; Yamada, K

EUROPEAN JOURNAL OF PHARMACOLOGY Vol. 931 page： 175207 2022.9

Language：English Publisher：European Journal of Pharmacology

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.

DOI： 10.1016/j.ejphar.2022.175207

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PubMed

A machine learning model that emulates experts' decision making in vancomycin initial dose planning Reviewed Open Access

Matsuzaki, T; Kato, Y; Mizoguchi, H; Yamada, K

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 148 ( 4 ) page： 358 - 363 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Pharmacological Sciences

Vancomycin is a glycopeptide antibiotic that is a primary treatment for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness and prevent nephrotoxicity, therapeutic drug monitoring (TDM) of trough concentrations is recommended. Initial vancomycin dosing regimens are determined based on patient characteristics such as age, body weight, and renal function, and dosing strategies to achieve therapeutic concentration windows at initial TDM have been extensively studied. Although numerous dosing nomograms for specific populations have been developed, no comprehensive strategy exists for individually tailoring initial dosing regimens; therefore, decision making regarding initial dosing largely depends on each clinician's experience and expertise. In this study, we applied a machine-learning (ML) approach to integrate clinician knowledge into a predictive model for initial vancomycin dosing. A dataset of vancomycin initial dose plans defined by pharmacists experienced in vancomycin TDM (i.e., experts) was used to build the ML model. Although small training sets were used, we established a predictive model with a target attainment rate comparable to those of experts, another ML model, and commonly used vancomycin dosing software. Our strategy will help develop an expert-like predictive model that aids in decision making for initial vancomycin dosing, particularly in settings where dose planning consultations are unavailable.

DOI： 10.1016/j.jphs.2022.02.005

New Strategies for the Treatment of Neuropsychiatric Disorders Based on Reelin Dysfunction Reviewed Open Access

Tsuneura, Y; Nakai, T; Mizoguchi, H; Yamada, K

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol. 23 ( 3 ) 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences

Reelin is an extracellular matrix protein that is mainly produced in Cajal-Retzius cells and controls neuronal migration, which is important for the proper formation of cortical layers in the developmental stage of the brain. In the adult brain, Reelin plays a crucial role in the regulation of N-methyl-D-aspartate receptor-dependent synaptic function, and its expression decreases postnatally. Clinical studies showed reductions in Reelin protein and mRNA expression levels in patients with psychiatric disorders; however, the causal relationship remains unclear. Reelin-deficient mice exhibit an abnormal neuronal morphology and behavior, while Reelin supplementation ameliorates learning deficits, synaptic dysfunctions, and spine loss in animal models with Reelin deficiency. These findings suggest that the neuronal deficits and brain dysfunctions associated with the down-regulated expression of Reelin are attenuated by enhancements in its expression and functions in the brain. In this review, we summarize findings on the role of Reelin in neuropsychiatric disorders and discuss potential therapeutic approaches for neuropsychiatric disorders associated with Reelin dysfunctions.

DOI： 10.3390/ijms23031829

Mice with exonic RELN deletion identified from a patient with schizophrenia have impaired visual discrimination learning and reversal learning in touchscreen operant tasks Reviewed

Liao, JZ; Dong, GY; Wulaer, B; Sawahata, M; Mizoguchi, H; Mori, D; Ozaki, N; Nabeshima, T; Nagai, T; Yamada, K

BEHAVIOURAL BRAIN RESEARCH Vol. 416 page： 113569 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Behavioural Brain Research

The Reelin gene (RELN) encodes a large extracellular protein, which has multiple roles in brain development and adult brain function. It activates a series of neuronal signal transduction pathways in the adult brain that function in synaptic plasticity, dendritic morphology, and cognitive function. To further investigate the roles of Reln in brain function, we generated a mouse line using the C57BL/6 J strain with the specific Reln deletion identified from a Japanese patient with schizophrenia (Reln-del mice). These mice exhibited abnormal sociality, but the pathophysiological significance of the Reln deletion for higher brain functions, such as learning and behavioral flexibility remains unclear. In this study, cognitive function in Reln-del mice was assessed using touchscreen-based visual discrimination (VD) and reversal learning (RL) tasks. Reln-del mice showed normal learning in the simple VD task, but the learning was delayed in the complex VD task as compared to their wild-type (WT) littermates. In the RL task, sessions were divided into early perseverative phase (sessions with <50% correct) and later learning phase (sessions with ≥50% correct). Reln-del mice showed normal perseveration but impaired relearning ability in both simple RL and complex RL task as compared to WT mice. These results suggest that Reln-del mice have impaired learning ability, but the behavioral flexibility is unaffected. Overall, the observed behavioral abnormalities in Reln-del mice suggest that this mouse model is a useful preclinical tool for investigating the neurobiological mechanism underlying cognitive impairments in schizophrenia and a therapeutic strategy.

DOI： 10.1016/j.bbr.2021.113569

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Dynamic changes in orexin activities associated with reward-based motivative behavior

Yutao Dong, Mizoguchi Hiroyuki, Yamanaka Akihiro, Yamada Kiyofumi

Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. 95 ( 0 ) page： 1-SS-08 2022

Language：Japanese Publisher：Japanese Pharmacological Society

Orexin neurons in the hypothalamus regulate physiological functions, including energy homeostasis and wakefulness, and are also related to motivation. Here, we examined the roles of orexin neurons in motivated behaviors. We measured the activities of orexin neurons using fiber photometry under a free-moving condition, in which the rats were subjected to the fixed ratio (FR) or progressive ratio (PR) schedule of a touchscreen-based automated operant task. To measure the activities of orexin neurons, AAV-FLEX-GCaMP7s was injected into the hypothalamus of Orexin-Cre rats. We found that under FR5 conditions in which rats were able to obtain a food pellet by touching the screen consecutively five times, the activity in orexin neurons was increased after the fifth screen touch (after which one food pellet is delivered). The activity peaked before rats obtained reward, and then decreased after food intake. Next, we included non-reward trials in the FR5 test in which the rat was not able to earn reward even after touching the screen five times. The orexin activities in non-reward trials were also increased after the fifth screen touch, but the decrease after food intake was diminished compared to those in reward-trials. In the PR schedule test, the orexin activities were gradually increased. Together, these observations suggest that the orexin activities are associated with motivational behaviors, and that orexin neurons may be involved in craving and reward prediction, and satisfaction.

DOI： 10.1254/jpssuppl.95.0_1-ss-08

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<MIZOGUCHI, Hiroyuki>

Papers - MIZOGUCHI, Hiroyuki