著者

今井 英明 Nina Dedic Heather Dworak Seth Hopkins Courtney Zeni Kenneth Koblan

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-B-S21-2, 2022 (Released:2022-12-26)

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Since the discovery of chlorpromazine, antagonism of dopamine D2 receptors has been central to the mechanism of antipsychotic drug efficacy. Currently approved antipsychotics effectively manage the positive symptoms of schizophrenia, however, their effects on negative and cognitive symptoms are negligible. Moreover, these drugs are associated with many serious side effects (e.g., motor and endocrine abnormalities, sedation, and weight gain) which negatively impact medication adherence. Researchers have vigorously pursued new therapeutic targets to treat schizophrenia beyond D2 receptor blockade. Recently, trace amine-associated receptor1 (TAAR1) has emerged as a promising new drug target. This review will discuss the current state of research of TAAR1 and will summarize the status of TAAR1 agonists in clinical development and their potential treatments for psychiatric disorders. Ulotaront is a TAAR1 agonist with 5-HT1A agonist activity under investigation for the treatment of schizophrenia. Ulotaront is the first TAAR1 agonist to progress to randomized controlled clinical trials and has demonstrated broad efficacy in animal models of schizophrenia. Unlike all approved antipsychotic drugs, ulotaront does not exert its effects via blockade of dopamine D2 or serotonin 5-HT2A receptors. In a randomized, double-blind, placebo-controlled clinical trial in patients with an acute exacerbation of schizophrenia, ulotaront demonstrated efficacy for both positive and negative symptoms, with continued symptom improvement observed over the course of the optional 6-month open-label extension study. In these studies, ulotaront was generally safe and well-tolerated with a tolerability profile similar to placebo and distinguished from the antipsychotic class, supporting its novel mechanism of action and absence of D2-receptor blockade. Taken together, these results are supportive of the therapeutic potential of TAAR1 agonists as a possible new drug class for the treatment of schizophrenia.

著者

衣斐 大祐

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.4-B-S43-2, 2022 (Released:2022-12-26)

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Serotonergic psychedelics such as psilocybin, the psychoactive substance found in the magic mushroom, have hallucinatory effect through stimulation of the cortical serotonin 5-HT2A receptor (5-HT2A). Recently, FDA has called psilocybin a 'breakthrough therapy' for severe depression. We have already demonstrated that 5-HT2A in the lateral septum (LS) plays a responsible role in antidepressant-like effect of psilocin, an active metabolite of psilocybin, whereas hallucinatory effect of psilocin was attributed to 5-HT2A stimulation in the visual cortex (V1) in mice. Here, we investigated the neural network responsible for antidepressant effect of psilocin. The histological study with anterograde and retrograde transports of adeno-associated viruses showed that 5-HT2A in LS abundantly expressed in GABAergic neurons, which projects to the dorsomedial hypothalamic nucleus (DM) in mice. Therefore, we investigated the functional role of 5-HT2A-positive LS-DM pathway in antidepressant effect by optogenetic and chemogenetic approaches. Selective inhibition of 5-HT2A-positive LS-DM pathway eliminated the antidepressant-like effect of psilocin in mice in forced-swim test as well as social defeat stress test. On the other hand, activation of the LS-DM pathway induced antidepressant-like effect in mice. Lastly, microinjection of bicuculline, an antagonist of GABAA receptor, into the DM diminished such effect of psilocin in mice. These suggest that 5-HT2A-positive LS-DM GABAergic network contributes to antidepressant effect of serotonergic psychedelics.

著者

今井 由美子

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-ES-4, 2020 (Released:2020-03-18)

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The respiratory virus infection COVID-19 caused by the new coronavirus SARS-CoV2 has been reported in China since December 2019. It has been reported that COVID-19 tends to be more severe in the elderly and in patients with underlying diseases including diabetes, heart disease, and chronic lung disease. In severe cases, patients require intensive cares including mechanical ventilation in the ICUs. So far, no biomarker that predicts the severity, or no therapeutic strategies to prevent the development of severe diseases has been established. Pathology of severe COVID-19 has two aspects: viral overgrowth and excess pulmonary inflammation. For the former, clinical trials using existing drugs such as remdesivir (nucleic acid drug), lopinavir/ritonavir combination drug (protease inhibitor), favipravir (polymerase inhibitor), and interferon (antiviral drugs) are being conducted in patients with severe COVID-19 in China. Furthermore the interest has been focused on immune globulin preparations enriched with pathogen-specific antibodies collected from the plasma of recovered patients. For the latter, clinical studies using tocilizumab (IL-6 receptor antibody) and ACE2 protein have been conducted with the purpose of reducing excessive inflammation of the lung. In addition, single cell analysis of immune cells and comprehensive repertoire analysis of TCR/BCR using patient blood are in progress overseas, which are useful to elucidate the mechanism of the severe disease progression and identify the useful biomarkers for it.

著者

島田 眞路

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-B-SL09, 2022 (Released:2022-12-26)

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わが国の科学技術力の衰退、低迷が止まらない。先日、世界各国のTop10%論文数が公表されたが、日本は長期低迷傾向にあり、今年は2カ国に抜かれ、10位から12位となってしまった。何とヨーロッパ諸国の中で後塵を拝してきたスペインとアジアの隣国韓国に抜かれたのである。その原因は、国の科学技術研究費を抑制してきた財務省/文科省にある。国立大学法人化をきっかけに、国立大学運営費交付金を2004年から毎年1%減らし続け、現在では10%以上減額となっている。厚労省も基礎医学研究に対してバッシングを行い続け、卒後臨床研修制度=大学否定、日本専門医機構=学会否定を行ってきた。このアカデミズム否定は、かつての文化大革命を想起させる暴挙である。これらの政策のおかげで日本の研究力は顕著に低下した。そのよい例が今般の新型コロナウイルス感染症対応で露わになった。ワクチン、治療薬ともその開発は、欧米に大きく遅れをとってしまった。これらの科学技術研究を中心とするアカデミズム抑制政策を即刻転換しなければ、日本の科学技術力は本当に地に堕ちる可能性があり、深く憂慮している。

著者

Tamiko Suzuki-Nishimura Masayoshi Baba Shiori Otani Arisa Yamamoto Yasushi Kodama

出版者

Japanese Pharmacological Society

雑誌

日本薬理学会年会要旨集 (ISSN:24354953)

巻号頁・発行日

pp.PO3-4-11, 2018 (Released:2020-09-10)

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The manic depression drug lithium carbonate has many mechanisms of action. As one of these mechanisms is the inhibition of amine release from the end of synapses, we examined the effects of lithium carbonate on the IgE-independent histamine release from rat peritoneal mast cells. In the presence of 0.3 mM CaCl2, at concentrations from 0.3 to 3.0 mM, lithium carbonate inhibited the histamine release induced by bradykinin (BK) (10 μM), substance P (SP) (10 μM) or compound 48/80 (48/80) (1 μg/mL). The histamine release induced by 1 μg/mL of 48/80 was inhibited by lithium carbonate, but that by 5 μg/ml of 48/80 was not. The IgE independent activator GlcNAc-specific Datura stramonium agglutinin (DSA) releases histamine from rat mast cells similar with 48/80, and lithium carbonate also inhibited the histamine release induced by DSA at 100 μg/mL. BK, SP and 48/80 are well-known activators against MRGPR. Mouse MrgprB2 and human MRGPRX2 on mast cells are possible targets of the pseudo-allergic drug reactions involving mast cell activation. Rat peritoneal mast cells have similar MRGPR calcium-dependent and calcium-independent pathways for mast cell activation. Inhibition of BK- or SP-induced histamine release by lithium carbonate did not recover after increasing the extracellular calcium concentration, suggesting that MRGPR in rat mast cells may be a calcium-independent, G-protein dependent receptor. The effects of lithium carbonate suggested that lithium carbonate inhibited downstream of the common signal transduction pathway, following MRGPR activation induced by BK, SP, 48/80 or DSA. The clinical dose of lithium carbonate is from 0.5 to 1 mM, and addiction occurs from 1.8 to 2.5 mM. The inhibitory effects of lithium carbonate on the IgE-independent histamine release were observed at both the clinical and addictive doses in humans, suggesting that lithium carbonate similarly inhibits both histamine release from mast cells and brain amine release from synapses.

著者

縄田 陽子 安作 美香 西奥 剛 山口 拓

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-P-035, 2022 (Released:2022-03-21)

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Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disability that demonstrates impaired social interactions, social communication deficits, and restrictive/repetitive behaviors. The endocannabinoid (eCB) system in the brain is a major regulator of synaptic plasticity and neuromodulation. It is reported that the eCB system have been altered in children with ASD and some animal models of ASD. To determine the causal role of the eCB system in the ASD, we have investigated the relationship between declines of the eCB system and the ASD-like symptoms, using the cannabinoid CB1 receptor knockout (CB1KO) mice. We found that male CB1KO mice demonstrated reduced sociability (3-chambered social approach task), elevated repetitive grooming behaviors (hole-board test) and deficits in short-term memory (Y-maze test). Moreover, the CB1KO mice also showed emotional instabilities (elevated plus-maze test and hole-board test). The serum progranulin, which is lower levels in patients of ASD, was significantly decreased in CB1KO mice. These findings suggested that CB1KO mice showed behavioral phenotypes including social deficits, which have face validity as an animal model of ASD. Therefore, the CB1KO mice will be a valuable tool for the exploration of pathological mechanisms and development of novel therapeutics in the ASD.

著者

岡部 繁男

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-SL03, 2022 (Released:2022-03-21)

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生体内での神経回路の発達には、シナプスの形成、除去、再構築が正確に制御されていることが重要である。マウスの大脳皮質では、シナプスの動態に2つの段階があることが、2光子イメージングによって確認された。第1期(生後20日まで)では、シナプスのターンオーバーが高く維持され、第2期(生後3週間以降)では、シナプス動態が強く抑制され、大脳皮質の神経ネットワークとしての成熟が起こる。このようなシナプス動態の変遷は、神経発達障害や精神疾患の病態生理の背景にあると考えられているが、その正確なメカニズムはまだ明らかになっていない。私たちの研究室では、(1)神経回路やシナプス形成過程の多様なメカニズム、(2)シナプスの動的変化の過程での構造・機能連関、(3)脳疾患とシナプス機能障害の関係、に焦点を当てて研究を行っている。最近では、スパインシナプスの超微細構造を定量的に解析する方法や、スパイン内部の分子ダイナミクスを測定する方法など、神経回路を研究するための新しいツールを開発している。さらに、これらのツールは脳疾患の研究にも応用可能である。本講演では、これらの研究を紹介するとともに、精神疾患の病態をシナプス障害として理解することの妥当性と展望について議論したい。

著者

竹田 誠

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-ES-1, 2020 (Released:2020-03-18)

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In December 2019 a pneumonia outbreak by the novel coronavirus, SARS-CoV-2, occurred in Wuhan City, China. The disease was named as COVID-19. Information on the SARS-CoV-2 genomic sequence was first released on 10 January 2020. We urgently started development of genetic diagnostic methods for SARS-CoV-2. On 14 January, soon after receiving the prototype designed primers, we have received the first clinical specimens suspected for COVID-19. We urgently started assessment of the primers and the laboratory diagnosis testing for SARS-CoV-2 in a parallel way. After the nightlong assessment/testing, the first COVID19 case in Japan was confirmed. The patient was a returnee from Wuhan. Until 22 January, we have established the nested RT-PCR diagnostic method/protocol for SARS-CoV-2, and urgently distributed the primer set/protocol to ~ 80 prefectural public health laboratories (PHLs) nationwide, because the Chun Jie holidays starts in China on 24 January and many Chinese tourists visit Japan. As we concerned, sporadic COVID-19 cases with an epidemiological linkage to Wuhan have detected in Tokyo, Aichi, Nara, Hokkaido, and Osaka prefectures after 24 January. Following the nested RT-PCR method, we have established the real-time RT-PCR diagnostic methods for SARS-CoV-2, and distributed the primer/probe set to ~ 80 PHLs on 30–31 January. However, the laboratory workload increased dramatically, because Japan has started to accept 829 returnees (15 were shown to be SARS-CoV-2-positive later) from Wuhan using government chartered flights on 29 January and screen ~3,500 passengers and crew (>600 were shown to be SARS-CoV-2-positive later) on a cruise ship quarantined in Yokohama for SARS-CoV-2. About one month and a half has passed, a significant number of COVID-19 cases via unknown infection route are currently detected in many prefectures in Japan (total 239 cases, as of 2 March 2020).

著者

牛尾 聡一郎 北村 佳久 江角 悟 座間味 義人

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-P-062, 2022 (Released:2022-03-21)

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Hochuekkito (HET), a Kampo medicine, is used to treat post-operative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and inflammation. However, the mechanism underlying the anti-anxiety effect of HET is unknown. In this study, we revealed the effect of HET on lipopolysaccharide (LPS) -induced anxiety-like behavior and examined the mechanism underlying LPS induced anxiety-like behaviors. Following the administration of LPS (300 µg/kg, i.p.), mice demonstrated inflammation-induced anxiety-like behaviors in hole-board and light-dark box tests. Systemic administration of LPS increased the serum levels of interleukin-6. Repeated administration of HET (1.0 g/kg, p.o.) once a day for 2 weeks before LPS treatment ameliorated anxiety-like behavior and reduced LPS-induced serum levels of interleukin-6 in 5 h after LPS treatment. Additionally, HET decreased LPS-induced secretion of interleukin-6 in human macrophage cell line (THP-1) and mouse macrophage cell line (RAW264.7) as in mouse models. Therefore, our findings suggest that HET may be useful in treating inflammation-induced anxiety-like behavior.

著者

丹羽 俊朗 柳井 檀 杉本 静也 雫 真里菜

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第92回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P-128, 2019 (Released:2020-03-20)

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[Purpose] CYP2D catalyze dopamine formation from p- and m-tyramine in the brain, and human CYP2D6 is polymorphic Imipramine, a tricyclic antidepressant, and fluvoxamine, an SSRI, are CYP2D6 inhibitors. Dopamine formation from p-tyramine mediated by CYP2D6 variants, CYP2D6.2 and CYP2D6.10 was compared, and the effect of genetic polymorphism on the inhibitory effects of antidepressants was investigated.[Methods] CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were used. Dopamine formation from p-tyramine in the presence of antidepressants such as imipramine, desipramine, fluvoxamine, fluoxetine, and paroxetine was determined by HPLC.[Results] CYP2D6.10 had higher Michaelis constants of dopamine formation than CYP2D6.1 and CYP2D6.2. Inhibition constant of imipramine and desipramine against CYP2D6.10 were higher than that against CYP2D6.1. Fluoxetine and paroxetine inhibited CYP2D6.1-mediated dopamine formation. The maximal velocity for all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations. [Conclusions] CYP2D6 polymorphism might affect the inhibitory effect of antidepressants on dopamine formation in the brain.

著者

高田 真優子 西村 周泰 高田 和幸

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第94回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-P1-21, 2021 (Released:2021-03-21)

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Alzheimer’s disease (AD) is an age-related neurodegenerative disease that is characterized by formation of amyloid-β (Aβ) plaque and neurofibrillary tangle. These pathological events cause neural cell death and progressive cognitive impairment. While, microglia are the resident macrophages of central nervous system and have the function of Aβ phagocytosis. Although AD animal models have been used to investigate pathophysiology of AD, they show limitations on recapitulating the complexity of human brain microenvironment. Especially, interaction of neurons and microglia is still poorly understood in both normal and AD. Here we generated 3D co-culture organoid system mimicking human brain microenvironment with human induced pluripotent stem cell (iPSC)-derived cerebral organoid and primitive macrophages. First, we separately generated cerebral organoids and macrophage from iPSCs and co-cultured them in single dish. The organoid expressed cerebral cortex-specific genes and showed multi-layer structure, and primitive macrophages exhibited microglia-like morphology and interacted with the neurons in the organoid. Therefore, 3D co-culture system is useful model for greater understanding interaction of neurons and microglia. Our 3D co-culture model system will be also applicable for AD modeling and developing novel therapies against AD.

著者

井上 里加子 小川 亜紀 吉村 征浩 入江 康至

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第92回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-P-134, 2019 (Released:2020-03-20)

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There are two types of amazake: malted-rice amazake and Sake lees amazake. It has been reported that Sake lees amazake improves human intestinal flora and relieves constipation. But there is no report on malted-rice amazake for improving constipation. The purpose of this study is to conduct a long-term ingestion test on humans and consider whether intake of malted-rice amazake will improve constipation. The subject is adult females with periodic menstrual cycles. Feces were collected in the follicular phase to minimize the influence of premenstrual syndrome. The DNA extracts from feces were analyzed using quantitative PCR using specific primers. The defecation status was investigated by self-report questionnaire.In the defecation state, soft stool of the stool was found significantly by intake of malted-rice amazake in hard stool group. Symptoms of constipation improved in 83% of constipation group. Analysis of intestinal bacterial flora showed a significant decrease the ratio of Firmiscutes / Bacteroidetes in constipation group due to intake of malted-rice amazake. It was suggested that intake of malted-rice amazake changed the construction of gut microbiota as well as the intestinal environment, resulting in improvement in constipation.

著者

関口 拓己 櫻井 隆 山下 直也

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第96回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.4-B-P-301, 2022 (Released:2022-12-26)

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Amyloid-beta (Aβ) aggregation has been believed to be the fundamental trigger of the development of Alzheimer's disease (AD). Therefore, elucidating the mechanisms that induce Aβ overproduction from its type I transmembrane precursor protein (APP) is one of the important issues in providing potential therapeutic targets for AD. Semaphorin3A (Sema3A), a secreted type of repulsive axon guidance molecule, is implicated in the development of various neurodegenerative diseases. It was previously reported that Sema3A and its signaling molecules accumulate and aggregate in AD patients' brain. However, the molecular link between Sema3A signaling and AD pathogenesis remains unknown. Here we show evidence that APP interacts with PlexinA, a Sema3A receptor component. APP and PlexinA interacted through the extracellular regions and we were able to narrow down these regions to less than 100 amino acids. Based on these findings, we are now investigating whether the APP-PlexinA interaction affects APP function and metabolism, which might provide new perspective that aberrant Sema3A signaling induces Aβ overproduction.

著者

倉本 展行 林 亮佑 金城 俊彦 宇野 恭介

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第94回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-O-B1-4, 2021 (Released:2021-03-21)

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Intracellular (cytosolic) potassium ion concentration is higher than extracellular space, since it is regulated by transport proteins on cell membranes such as sodium pumps. Therefore, potassium channel opening on the cell membrane lowers the intracellular potassium ion concentration by allowing potassium to flow out of the cell. On the other hand, the potassium concentration in the mitochondrial matrix is ​​lower than that in the cytosol. Therefore, the mitochondrial membrane permeable transition pore (PTP) opening of the inner mitochondrial membrane flows into the potassium matrix and depolarizes the inner membrane. Excessive depolarization of the inner membrane induces cell death. Therefore, in this study, we investigated the possibility that the decrease in intracellular potassium concentration suppresses cell death caused by mitochondrial depolarization. NMDA exposure to primary cortical neurons induced mitochondrial depolarization and neuronal cell death with increased intracellular calcium concentration, which was suppressed by pretreatment of GABAB receptor agonists. The neuronal cell death inhibitory effect of GABAB receptor agonists was suppressed by the G protein-activating potassium channel inhibitor tertiapin, not by the adenylate cyclase activator forskolin. In addition, the ATP-sensitive potassium channel opener minoxidil significantly reduced intracellular potassium levels and suppressed mitochondrial depolarization and neuronal cell death associated with NMDA exposure. From the above, it is suggested that reducing the intracellular potassium level suppresses neuronal cell death mediated by mitochondrial depolarization due to excitatory stimulation.

著者

森谷 美穂 橋本 璃乃 前田 桜 松木 亨 関 健二郎

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第93回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P-293, 2020 (Released:2020-03-18)

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Re-experiencing trauma by overgeneralization is a hallmark of PTSD which is high comorbidity with depression. We thus studied the relation from overgeneralization to depression. Mice were subjected to context A with electric shock as a conditioning which was followed by unconditioned context B using a different, but similar box in 3h on Day1 and was followed by re-exposure to context A (Group ABA) or B (Group ABB) on Day2. Group ABA and ABB mice exhibited the longer freezing in context A and B on Day2. However, the mice which was not exposed to context B on Day1 (Group A-B) showed the shorter freezing time in context B on Day2, indicating that the overgeneralization was induced by experiencing the context B after the conditioning in 3 h. Group ABB mice exhibited the longer immobility time of tail suspension test (TST) than Group ABA and A-B. Freezing time in the first half of the test in context B and immobility time of TST in Group ABB were negatively correlated with the staying time of center zone in the box during the context B on Day1. In contrast, the freezing and immobility time of TST in Group ABA have positive correlation with the time of center zone during context B on Day1. These results suggest that the PTSD and depression may depend on the coping style during unconditioned context within a few hours after the trauma.

著者

細田 隆介 久野 篤史 中島 龍汰 朝倉 聖大 岩原 直敏 野島 伊世里 國本 梨沙 堀尾 嘉幸

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-YIA-44, 2022 (Released:2022-03-21)

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[Background] SIRT1, an NAD+-dependent deacetylase, positively regulates autophagy, which maintains muscle mass and declines with age. We previously reported that treatment with resveratrol (RSV), an activator of SIRT1, restores muscle autophagy and preserves muscle mass in a mouse model of Duchenne muscular dystrophy. We hypothesized that RSV attenuates age-related muscle atrophy by activating SIRT1 and autophagy.[Methods and Results] DDY mice were treated with either a control diet or a diet containing RSV (0.4 g/kg diet) from 23 weeks of age, and tissues of tibialis anterior muscle were analyzed at 60 weeks old. Rotarod running time was shortened with aging; however, RSV treatment preserved running time. RSV blocked the aging-related increase in acetylated lysine levels in muscles, suggesting that RSV restored deacetylase activity of muscle SIRT1. Compared with 20 weeks old mice, the myofiber diameter was decreased in untreated 60 weeks old mice. In addition, LC3-II/LC3-I ratio, a marker of autophagic activity, was decreased and p62 and ubiquitinated protein levels, which are degraded by autophagy, were increased in muscles of 60 weeks old mice, suggesting impaired autophagy by aging. RSV treatment preserved the myofiber diameter, increased LC3-II/LC3-I ratio, and decreased p62 and ubiquitinated protein levels. RSV did not change activities of signals that regulate autophagy including AMPK and mTORC1.[Conclusion] These results suggest that RSV attenuates age-related muscle atrophy and motor dysfunction by activating SIRT1 and promoting autophagy.

著者

Chie Sakanaka Ryoko Ihara Akiko Kishi Kenji Kirihara Gaku Oguri Mihoko Shibuya Kazushi Suzuki Keiko Ueda Yumi Umeda-Kameyama Mitsutaka Yakabe Tomohiro Haga Hidenori Yamasue

出版者

Japanese Pharmacological Society

雑誌

日本薬理学会年会要旨集 (ISSN:24354953)

巻号頁・発行日

pp.OR6-3, 2018 (Released:2020-09-10)

被引用文献数

3 4

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Background:Autism spectrum disorder (ASD) is a neurodevelopmental disorder, mainly exhibit problems in social communication/interaction behaviors. ASD is shown to affect one out of 100 individuals, however, the cause and the established treatments on the core symptoms of ASD are unavailable. Recently, peptide hormone Oxytocin showed some promises in treating ASD core symptoms, and various clinical studies are currently underway. The objective of this study is to evaluate the safety and pharmacokinetics of new formulation of intra-nasal Oxytocin in healthy Japanese male.Methods:In this double-blind, randomized, placebo-controlled Phase1 study, 5 cohorts of eight subjects received a single dose of intranasal TTA-121 at dose levels of 5, 10, 30, 100 and 200 U/ml or placebo and 3 cohorts of eight subjects received 30, 100 and 200 U/ml or placebo at repeated doses for 9 days. Safety assessments were conducted throughout the study.Results:Regarding safety, no serious adverse events were reported and no clinically significant findings were observed throughout the study. A linear relationship between plasma concentration of Oxytocin and administered dose of TTA-121 (5 to 200 U/ml) was observed. There was no drug accumulation after multiple doses of intra-nasal Oxytocin.Conclusions:TTA-121 was well tolerated and safe in Japanese healthy male subjects after administration of multiple doses up to 200U/ml, BID for 9 days.Trial Registration:UMIN000025922

著者

室井 喜景 石井 利明

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-P-029, 2022 (Released:2022-03-21)

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Maternal care is indispensable for survival of neonates in mammals. Lactating females consume a large amount of energy for nurturing their pups by lactation. Management of energy expenditure through lactation is important for survival of themselves and pups. We previously reported that the orexigenic neuropeptide neuropeptide Y in the dorsal raphe nucleus (DRN) regulated maternal care, depending on food intakes of lactating females. In the present study, we investigated the neuronal mechanism for regulating maternal care by melanocortin 3 and 4 receptors (MC 3/4R), which was regulated by the anorexigenic neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) and the orexigenic neuropeptide agouti-related peptide (AgRP) in an opposing manner. Neuronal processes immunoreactive to adrenocorticotropic hormone, which was a precursor of α-MSH, or AgRP, were distributed in the DRN. Furthermore, the pre-synaptic marker synaptophysin was co-localized with ACTH or AgRP in the DRN. We next investigated how the MC3/4R antagonist SHU 9119 affected maternal care. Injection of 100 pmol SHU 9119 into the DRN prevented maternal care in fed dams. Additionally, we examined whether the agonist melanotan II could affect maternal care following fasting for 8 h. Fasting for 8 h abolished maternal care in lactating females. But injection of 100 pmol melanotan II into the DRN partially recovered maternal care. These results indicate that MC3/4R signaling in the DRN regulates maternal care depending on feed intake in lactating mice.

著者

橋本 謙二

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第95回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-EL01, 2022 (Released:2022-03-21)

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近年、麻酔薬ケタミンがうつ病の画期的な治療薬として注目されている。ケタミンは治療抵抗性うつ病患者に投与して数時間後に抗うつ効果を示し、その効果は1週間以上持続する。さらに、ケタミンはうつ病患者の自殺願望、希死念慮も劇的に改善し、自殺予防という点からも注目されている。ケタミンは、不斉炭素を有しているので、二つの光学異性体を有する。わが国で使用されている麻酔薬ケタミンはラセミ体である。米国Johnson & Johnson社は、NMDA受容体への親和性が強いエスケタミンを開発し、2019年に治療抵抗性うつ病の治療薬として、米国と欧州で承認された。一方、演者らはNMDA受容体への親和性が弱いアールケタミンの方が、エスケタミンより抗うつ作用が強く、副作用が少ないことを発見した。現在、米国企業がアールケタミンの第二相臨床治験を海外で実施中であり、わが国では大塚製薬株式会社が第一相臨床治験を準備中である。本教育講演では、千葉大学で開発した新規抗うつ薬アールケタミンの最新知見について議論したい。

著者

竹下 舜也 日比 千尋 坂本 多穗 黒川 洵子

出版者

公益社団法人 日本薬理学会

雑誌

日本薬理学会年会要旨集 第94回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.3-P2-25, 2021 (Released:2021-03-21)

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Intensive care unit-acquired weakness (ICU-AW) is a sepsis-induced myopathy characterized by reductions in muscle force-generation, mass, and bioenergetics, leading to severe difficulties in breathing, swallowing, and exercise. Since males are more prone to sepsis and aromatase inhibitors worsen critical illness, we investigated the effect of 17β-estradiol (E2) on septic symptoms in skeletal muscle in an in vivo and in vitro. E2 treatment attenuated cecal ligation puncture (CLP)-induced loss of grip strength in ovariectomized (OVX) mice and preserve contractility of extensor digitorum longus muscle from OVX mice underwent CLP. E2 significantly attenuated lipopolysaccharide (LPS)-induced atrophy and induction of inflammatory cytokine mRNAs (TNFα and IL6) in mouse C2C12 myotubes. Furthermore, E2 significantly inhibited the LPS-induced increase of mtDNA, a driver of pro-inflammatory signals. Our results show that E2 attenuates inflammation through mitochondrial protection by inhibiting the increase in mtDNA, which also attenuates muscle weakness and atrophy. We anticipate that our results will lead to a more detailed mechanism analysis of attenuation of muscle weakness and atrophy by E2, as well as to elucidate gender differences in sepsis-induced ICU-AW.