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)

---

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

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)

---

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

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)

---

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.

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)

---

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

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)

---

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

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

---

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.