著者

川畑 伊知郎

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94回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.1-YAL1, 2021 (Released:2021-03-21)

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高齢化社会をむかえパーキンソン病の増加が社会問題であるが、根本的治療薬は未開発でありその開発が期待されている。私たちはパーキンソン病の発症機構の解明と治療薬の開発において、ドパミン神経選択的な変性メカニズムの解明、ドパミン機能を制御する新たな分子機構の発見、新たな創薬標的を用いた治療薬の薬理学的研究に取り組んできた。具体的に、ドパミン生合成の律速酵素であるチロシン水酸化酵素が中脳ドパミン神経で消失する新たな分子機構、消失したドパミン生合成酵素を回復するための新たな創薬標的の探索とドパミン作動性機能を制御する新規シグナルネットワーク、さらにパーキンソン病の原因タンパク質αシヌクレインが中脳ドパミン神経に取り込まれ伝播する新たなメカニズムを明らかにし、パーキンソン病の予防・治療応用が期待される。これらの研究成果から、パーキンソン病を含むレビー小体疾患の克服とその創薬研究、今後の展望について紹介する。

著者

宮崎 育子 磯岡 奈未 和田 晃一 菊岡 亮 北村 佳久 浅沼 幹人

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92回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-P-050, 2019 (Released:2020-03-20)

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Epidemiological studies showed that daily drinking coffee or teas decreases the risk of Parkinson's disease (PD) to 40-50%. Caffeic acid (CA) and chlorogenic acid (CGA) are coffee ingredients and exert antioxidative properties. Exposure to pesticides, such as rotenone, is an environmental factor that plays an important role in the pathogenesis of PD. In this study, we examined neuroprotective effects of CA and CGA against rotenone-induced neurodegeneration. Chronic subcutaneous injection of rotenone into C57BL/6J mice exhibited reduction of dopaminergic neurons in the substantia nigra and beta-tubulin III-positive neurons in the intestinal myenteric plexus. Daily oral administrations of CA or CGA inhibited rotenone-induced cell death of not only nigral dopaminergic neurons but also myenteric plexus. In addition, CA or CGA significantly increased expression of antioxidative molecule metallothionein in the striatal astrocytes. In coculture of neurons and astrocytes from the mesencephalon or intestine, CA and CGA inhibited rotenone-induced neuronal loss of mesencephalic dopaminergic and enteric neurons, respectively. These results suggest that daily intake of coffee ingredients prevents or delays the onset of PD.

著者

石田 恵子 山本 征輝 三沢 憲佑 西村 瞳 三澤 幸一 山本 尚基 太田 宣康

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-O-C3-3, 2021 (Released:2021-03-21)

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Epidemiological studies have revealed that habitual coffee consumption may reduce the risk of Alzheimer’s disease. Coffee includes many phenolic compounds (coffee polyphenols) such as chlorogenic acids. However, the contribution of chlorogenic acids to the prevention of cognitive dysfunction induced by Alzheimer’s disease remains obscure. In this study, we investigated the effect of chlorogenic acids on cognitive function in APP/PS2 transgenic mouse model of Alzheimer’s disease. Five-week-old APP/PS2 mice were administered a diet supplemented with coffee polyphenols daily for 5 months. The memory and cognitive function of mice was examined using the novel object recognition test, Morris water maze test, and the step-through passive avoidance test. Chronic treatment with coffee polyphenols prevented cognitive dysfunction and significantly reduced the amount of amyloid β (Aβ) plaques in the hippocampus. Moreover, 5-caffeoylquinic acid (5-CQA), one of the primary coffee polyphenols, did not inhibit Aβ fibrillation; however, degraded Aβ fibrils. Computational docking simulation predicted that 5-CQA interacted with specific amino acid residues in Aβ protofilament.  In conclusion, our results demonstrate that coffee polyphenols prevent cognitive dysfunction and reduce Aβ plaque deposition via disaggregation of Aβ in the APP/PS2 mouse.

著者

金子 周司 長島 卓也

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92回日本薬理学会年会 (ISSN:24354953)

巻号頁・発行日

pp.2-AS1-2, 2019 (Released:2020-03-20)

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FAERS is a public database that accumulates more than 9 million self-reports of adverse events. In nearly half of the cases, multiple drugs are prescribed, so that potential drug-drug interactions are to be analyzed. Focusing on adverse reactions relating to diabetes mellitus (DM) caused by an anti-schizophrenic quetiapine, we found that concomitant use of vitamin D analogs significantly suppresses the occurrence of quetiapine-induced DM in FAERS. Experimental validation revealed that quetiapine acutely caused insulin resistance, which was mitigated by dietary supplementation with cholecalciferol. In an expression database, several genes downstream of insulin receptor were downregulated by quetiapine. Further experiments clarified that a PI3K regulatory protein gene, pik3r1, was downregulated by quetiapine, which was reversed by cholecalciferol in mouse skeletal muscle. In addition, insulin-stimulated glucose uptake into cultured myotubes was inhibited by quetiapine, which was reversed by pretreatment with calcitriol. These results suggest that vitamin D prevents the atypical antipsychotic-induced hyperglycemia and insulin resistance by upregulation of PI3KR1. Until now, we have obtained several combinations of concomitant medications to reduce specific adverse events by FAERS analysis. This new strategy will pave the way for drug repositioning and clarifying unknown disease mechanisms.

著者

Julio C Almanza-Perez Beatriz Mora-Ramiro Wendoline Rosiles-Alanis Francisco J Alarcon-Aguilar Jose L Ventura-Gallegos Luis E Gomez-Quiroz Alejandro Zentlla-Dehesa

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.PO3-10-20, 2018 (Released:2020-09-10)

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BACKGROUNDThe chronic inflammatory process is a critical characteristic in several diseases. This condition has an important impact on the quality life of patients, as well as on their economic and social state. Patients in this condition use several anti-inflammatory agents, which are classified according to their chemical nature as steroidal (SAIDs) and non-steroidal (NSAIDs). However, It has been reported that its clinical use can generate dangerous adverse effects. For this motive, people use medicinal plants as an alternative of treatment. Several plants have been traditionally used as anti-inflammatory agents worldwide. One example is Psacalium decompositum, which has been reported with anti-inflammatory and antidiabetic effects. In chemical studies, sesquiterpenic compounds have been isolated, being the cacalol the main compound, which is considered the responsible principle of the anti-inflammatory effect of this plant. However, the action mechanisms involved in the anti-inflammatory action of cacalol have not yet been explored.The aim of this investigation was to establish whether the anti-inflammatory action of cacalol involves the Nf-kB pathway, using an in vitro model.METHODSRAW 264.7 macrophages were cultured and pre-stimulated with LPS. Two hours after, the cells were treated with cacalol. The concentration and relative expression of cytokines were quantified by RT-PCR. The cytokines studied were TNF, IL-6, IL-1b and IL-10. The pohosphorylated subunit p65 of Nf-kB and its nuclear translocation were measured by EMSA.RESULTSThe mRNA expression of TNF, IL-6 and IL-1b were significantly decreased in the macrophages due to cacalol. The protein concentrations in the culture of the cytokines also decreased. No changes were detected in the mRNA expression and concentration of IL-10. The cacalol decreased the concentration of the phosphorylated p65 subunit as did the translocation of Nf-kB to the nucleus.CONCLUSIONSCacalol suppressed the concentrations of pro-inflammatory cytokines without affecting the anti-inflammatory cytokines. This could be associated with the inhibition of the Nf-kB pathway, since the levels of the phosphorylated p65 subunit were reduced. It is important to continue with the study of the factors involved in the regulation of said inhibition, as well as of other transcription factors involved in the anti-inflammatory action of cacalol.

著者

笠 純華 倉内 祐樹 田中 理紗子 春田 牧人 笹川 清隆 関 貴弘 太田 淳 香月 博志

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-P1-07, 2021 (Released:2021-03-21)

被引用文献数

1

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Migraine is a common neurovascular disorder characterized by severe headaches and is associated with dysfunction of the autonomic nervous system. Notably, some patients who have migraine seem to be more sensitive to changes in the weather such as atmospheric pressure and humidity. Here, we investigated the effect of Goreisan, a traditional Kampo medicine used to treat headaches, on the cerebral blood flow (CBF) dynamics by using implantable CMOS imaging device for detecting hemodynamic signal in female meteoropathy model mice. Moreover, we evaluated the effect of loxoprofen, an analgesic used to treat headaches, on the CBF changes and compared it to the effect of Goreisan. To reproduce the change of the weather, atmospheric pressure was lowered by 50 hPa and kept this level for 1 h and it was returned to the previous level. We observed the increase in CBF during low atmospheric pressure, which was prevented by Goreisan (1 g/kg, p.o.) as well as loxoprofen (4 mg/kg, p.o.). Although CBF gradually recovered to baseline after returning to normal atmospheric pressure, Goreisan, but not loxoprofen, lowered CBF below baseline. These results suggest that Goreisan is the headache therapeutic drug with a different action profile from loxoprofen in that it has a mechanism to actively reduce cerebral blood flow.

著者

中尾 駿介 中道 範隆 増尾 友佑 竹田 有花 松本 聡 鈴木 真 加藤 将夫

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-YIA-03, 2019 (Released:2020-03-20)

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The aim of the present study was to examine enhancement of learning and memory by oral administration of ergothioneine (ERGO), which is a hydrophilic antioxidant highly contained in golden oyster mushrooms and other foods, and systemically absorbed by its specific transporter OCTN1/SLC22A4 in daily life, with an aim to clarify its possible role as a neurotropic compound. After oral administration of ERGO in normal mice, the novel object test revealed a longer exploration time for the novel object than for the familiar object. Similar result was also confirmed in mice ingested with ERGO-free diet. Dietary-derived ERGO is present in the body without the administration, but the ERGO administration led to modest (3~4 times) increase in its concentration in plasma and hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I, and neurotrophin-3 and -5. The elevation of synapsin I was inhibited by tropomyosin receptor kinase inhibitor K252a. Thus, oral intake of ERGO may enhance object recognition memory, and this could occur at least partially through promotion of neuronal maturation in the hippocampus.

著者

久場 敬司 湊 隆文 韮澤 悟 佐藤 輝紀 山口 智和 渡邊 博之 今井 由美子 高橋 砂織

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-314, 2020 (Released:2020-03-18)

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Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system, critically involved in blood pressure regulation, heart function, lung injury, or fibrotic kidney disease. Recombinant human ACE2 protein (rhACE2), currently clinically evaluated to treat acute lung failure, is a glycosylated protein, requiring time- and cost-consuming protein production in mammalian cells. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is a novel ACE2-like enzyme to decrease angiotensin II levels in mice. Comparative analysis of protein 3D structures revealed that B38-CAP homologue shares structural similarity to mammalian ACE2 without any apparent sequence identity, containing the consensus HEXXH amino acid sequence of the M32 peptidase family. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides, with the same potency and kinetics as human ACE2. Treatment with B38-CAP reduced plasma angiotensin II levels and suppressed angiotensin II-induced hypertension, cardiac hypertrophy and fibrosis in mice. Moreover, continuous infusion of B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice, without any overt toxicity of liver and kidney. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, which exhibits ACE2-like functions in vitro and in vivo. These results indicate that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.

著者

山元 ひかり 入鹿山 容子 石川 有紀子 滑川 由紀子 根本 剛 田中 大夢 高橋 元樹 柳沢 正史

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.1-SS-05, 2020 (Released:2020-03-18)

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Loss of orexin-producing neurons in the lateral hypothalamus causes the chronic sleep disorder narcolepsy-cataplexy. Narcoleptic humans suffer from two major symptoms, excessive sleepiness and cataplexy in the active phase, and these symptoms in mouse models are manifested as sleep/wakefulness fragmentation and SOREMs (direct transitions from wakefulness to REM sleep), respectively. The neuropeptides orexin-A (OXA) and orexin-B (OXB) act on two receptors orexin type-1 receptor (OX1R) and orexin type-2 receptor (OX2R). Orexin receptor agonists are expected to be of potential value for treating human narcolepsy. Here, to confirm the fundamental strategy aimed at improving narcoleptic symptoms, we examined the association between orexin receptor subtypes and these symptoms by intracerebroventricular (ICV) administration of the OX2R-selective agonist [Ala11, D-Leu15]-OXB in orexin knockout mice. OXA and [Ala11, D-Leu15]-OXB similarly decreased the number of SOREMs. Further, transition frequencies between NREM sleep and wake states in narcoleptic model mice were similarly decreased. We confirmed in vivo that [Ala11, D-Leu15]-OXB did not activate OX1R-expressing LC noradrenergic neurons by Fos staining. Therefore, OX2R-selective agonism is sufficient to ameliorate narcoleptic symptoms, both cataplexy and fragmentation of wakefulness in model mice. Activation of LC noradrenaline neurons expressing OX1R are not essential for suppression of these symptoms.

著者

恒枝 宏史 前田 貴大 髙田 慎治郎 大塚 小由希 今 寛太 和田 努 笹岡 利安

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-O-050, 2020 (Released:2020-03-18)

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Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease induced by obesity. So far, no therapeutic drug is available against NASH, because the pathogenic mechanism remains unclear. Since hypothalamic orexin system is a main regulator of energy homeostasis, we investigated the role of orexin against NASH under obese conditions, using orexin knockout (ORX-KO) mice fed high fat diet (HFD). ORX-KO mice showed severer obesity and glucose intolerance on HFD, compared to wild-type controls. Also, remarkable NASH-like phenotypes were observed in the liver of ORX-KO mice, such as the accumulation of triglyceride and the increase in the levels of biomarkers for endoplasmic reticulum (ER) stress (phosphorylation of eIF2α, etc.), chronic inflammation (Tnfα mRNA, etc.), and hepatic fibrosis (Tgfβ mRNA, etc.). When the HFD-fed ORX-KO mice were treated with orexin A (i.c.v.), the hepatic ER stress and chronic inflammation were improved, whereas body weight was not altered. These results indicate that the central action of orexin is required to prevent the development of NASH by reducing ER stress and chronic inflammation in the liver under the obese condition. Hypothalamic orexin system may be a crucial therapeutic target to promote the brain-liver network functions for preventing the progression of NASH.