研究者基本情報

• 博士（獣医学）, 北海道大学

• https://researchmap.jp/reguchi88

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201901018420421615

• 10846067

• 201901018420421615

• ライフサイエンス, 薬理学
• ライフサイエンス, 獣医学

• 博士課程, 獣医学院

研究活動情報

• 2017年09月, 日本比較薬理学・毒性学会, 平成29年度日本比較薬理学・毒性学会奨励賞
  低Ca2+によるアストロサイトの細胞外アデノシン蓄積に対するFGF2の影響
  江口 遼太

• Epidermal growth factor increases cystathionine β-synthase expression in cultured embryonic spinal cord cells
  Ryota Eguchi; Yuya Higashida; Mizuki Oouchi; Soichiro Yamaguchi; Ken-ichi Otsuguro
  In Vitro Cellular & Developmental Biology - Animal, 61, 4, 416, 424, Springer Science and Business Media LLC, 2025年04月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）
• Short-term memory impairment following recovery from systemic inflammation induced by lipopolysaccharide in mice
  Kohei Morimoto; Shu Watanuki; Ryota Eguchi; Taisuke Kitano; Ken-ichi Otsuguro
  Frontiers in Neuroscience, 17, Frontiers Media SA, 2023年10月18日, ［査読有り］
  英語, 研究論文（学術雑誌）, The relationship between neuroinflammation and mental disorders has been recognized and investigated for over 30 years. Diseases of systemic or peripheral inflammation, such as sepsis, peritonitis, and infection, are associated with increased risk of mental disorders with neuroinflammation. To elucidate the pathogenesis, systemic administration of lipopolysaccharide (LPS) in mice is often used. LPS-injected mice exhibit behavioral abnormalities with glial activation. However, these studies are unlikely to recapitulate the clinical pathophysiology of human patients, as most studies focus on the acute inflammatory response with systemic symptoms occurring within 24 h of LPS injection. In this study, we focus on the effects of LPS on behavioral abnormalities following recovery from systemic symptoms and investigate the mechanisms of pathogenesis. Several behavioral tests were performed in LPS-injected mice, and to assess neuroinflammation, the time course of the morphological change and expression of inflammatory factors in neurons, astrocytes, and microglia were investigated. At 7 days post-LPS injection, mice exhibited short-term memory impairment accompanied by the suppression of neuronal activity and increases in morphologically immature spines. Glial cells were transiently activated in the hippocampus concomitant with upregulation of the microglial phagocytosis marker CD68 3 days after injection. Here we show that transient glial cell activation in the acute response phase affects neuronal activity and behavior following recovery from systemic symptoms. These findings provide novel insights for studies using the LPS-induced inflammation model and that will contribute to the development of treatments for mental disorders of this etiology.
• Dopamine regulates astrocytic IL-6 expression and process formation via dopamine receptors and adrenoceptors.
  Kohei Morimoto; Mai Ouchi; Taisuke Kitano; Ryota Eguchi; Ken-Ichi Otsuguro
  European journal of pharmacology, 928, 175110, 175110, 2022年06月20日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Dopamine levels in the central nervous system change under pathological conditions such as Parkinson's disease, Huntington's disease, and addiction. Under those pathological conditions, astrocytes become reactive astrocytes characterized by morphological changes and the release of inflammatory cytokines involved in pathogenesis. However, it remains unclear whether dopamine regulates astrocytic morphology and functions. Elucidating these issues will help us to understand the pathogenesis of neurodegenerative diseases caused by abnormal dopamine signaling. In this study, we investigated the effects of dopamine on IL-6 expression and process formation in rat primary cultured astrocytes and acute hippocampal slices. Dopamine increased IL-6 expression in a concentration-dependent manner, and this was accompanied by CREB phosphorylation. The effects of a low dopamine concentration (1 μM) were inhibited by a D1-like receptor antagonist, whereas the effects of a high dopamine concentration (100 μM) were inhibited by a β-antagonist and enhanced by a D2-like receptor antagonist. Furthermore, dopamine (100 μM) promoted process formation, which was inhibited by a β-antagonist and enhanced by both an α-antagonist and a D2-like receptor antagonist. In acute hippocampal slices, both a D1-like receptor agonist and β-agonist changed astrocytic morphology. Together, these results indicate that dopamine promotes IL-6 expression and process formation via D1-like receptors and β-adrenoceptors. Furthermore, bidirectional regulation exists; namely, the effects of D1-like receptors and β-adrenoceptors were negatively regulated by D2-like receptors and α2-adrenoceptors.
• Glu333 in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses.
  Yukari Itakura; Koshiro Tabata; Kohei Morimoto; Naoto Ito; Herman M Chambaro; Ryota Eguchi; Ken-Ichi Otsuguro; William W Hall; Yasuko Orba; Hirofumi Sawa; Michihito Sasaki
  iScience, 25, 4, 104122, 104122, 2022年04月15日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The amino acid residue at position 333 of the rabies virus (RABV) glycoprotein (G333) is a major determinant of RABV pathogenicity. Virulent RABV strains possess Arg333, whereas the attenuated strain HEP-Flury (HEP) possesses Glu333. To investigate the potential attenuation mechanism dependent on a single amino acid at G333, comparative analysis was performed between HEP and HEP333R mutant with Arg333. We examined their respective tropism for astrocytes and the subsequent immune responses in astrocytes. Virus replication and subsequent interferon (IFN) responses in astrocytes infected with HEP were increased compared with HEP333R both in vitro and in vivo. Furthermore, involvement of IFN in the avirulency of HEP was demonstrated in IFN-receptor knockout mice. These results indicate that Glu333 contributes to RABV attenuation by determining the ability of the virus to infect astrocytes and stimulate subsequent IFN responses.
• Alpha and beta adrenoceptors activate interleukin-6 transcription through different pathways in cultured astrocytes from rat spinal cord
  Kohei Morimoto; Ryota Eguchi; Taisuke Kitano; Ken-ichi Otsuguro
  Cytokine, 142, 155497, 155497, Elsevier BV, 2021年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Opposing functions of α- and β-adrenoceptors in the formation of processes by cultured astrocytes
  Taisuke Kitano; Ryota Eguchi; Yuko Okamatsu-Ogura; Soichiro Yamaguchi; Ken-ichi Otsuguro
  Journal of Pharmacological Sciences, 145, 3, 228, 240, Elsevier BV, 2021年03月, ［査読有り］, ［国内誌］
  英語, 研究論文（学術雑誌）, Astrocytes are glial cells with numerous fine processes which are important for the functions of the central nervous system. The activation of β-adrenoceptors induces process formation of astrocytes via cyclic AMP (cAMP) signaling. However, the role of α-adrenoceptors in the astrocyte morphology has not been elucidated. Here, we examined it by using cultured astrocytes from neonatal rat spinal cords and cortices. Exposure of these cells to noradrenaline and the β-adrenoceptor agonist isoproterenol increased intracellular cAMP levels and induced the formation of processes. Noradrenaline-induced process formation was enhanced with the α1-adrenoceptor antagonist prazosin and α2-adrenoceptor antagonist atipamezole. Atipamezole also enhanced noradrenaline-induced cAMP elevation. Isoproterenol-induced process formation was not inhibited by the α1-adrenoceptor agonist phenylephrine but was inhibited by the α2-adrenoceptor agonist dexmedetomidine. Dexmedetomidine also inhibited process formation induced by the adenylate cyclase activator forskolin and the membrane-permeable cAMP analog dibutyryl-cAMP. Moreover, dexmedetomidine inhibited cAMP-independent process formation induced by adenosine or the Rho-associated kinase inhibitor Y27632. In the presence of propranolol, noradrenaline inhibited Y27632-induced process formation, which was abolished by prazosin or atipamezole. These results demonstrate that α-adrenoceptors inhibit both cAMP-dependent and -independent astrocytic process formation.
• Hydrogen sulfide induces Ca2+ release from intracellular Ca2+ stores and stimulates lactate production in spinal cord astrocytes
  Takeshi Nii; Ryota Eguchi; Ken-ichi Otsuguro
  Neuroscience Research, 171, 67, 73, Elsevier BV, 2021年02月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Hydrogen sulfide (H2S) is a well-known inhibitor of the mitochondrial electron transport chain (ETC). H2S also increases intracellular Ca2+ levels in astrocytes, which are glial cells and that supply lactate as an energy substrate to neurons. Here, we examined the relationship between H2S-induced metabolic changes and Ca2+ responses in spinal cord astrocytes. Na2S (150 μM), an H2S donor, increased the intracellular Ca2+ concentration, which was inhibited by an ETC inhibitor and an uncoupler of mitochondrial oxidative phosphorylation. Na2S also increased the accumulation of extracellular lactate. Na2S alone did not change intracellular ATP content, but decreased it when glycolysis was inhibited. The Na2S-induced Ca2+ increase and accumulation of extracellular lactate were inhibited by emetine, an inhibitor of translocon complex, which mediates Ca2+ leak from the endoplasmic reticulum (ER). Furthermore, an inhibitor of the Ca2+-sensitive NADH shuttle decreased Na2S-mediated accumulation of lactate. We conclude that inhibition of the mitochondrial ETC by H2S induces Ca2+ release from mitochondria and the ER in spinal cord astrocytes, which increases lactate production. H2S may promote glycolysis by activating the Ca2+-sensitive NADH shuttle and facilitating the supply of lactate from astrocytes to neurons.
• Hydrogen sulfide induces Ca2+ release from the endoplasmic reticulum and suppresses ATP-induced Ca2+ signaling in rat spinal cord astrocytes
  Takeshi Nii; Ryota Eguchi; Soichiro Yamaguchi; Ken-ichi Otsuguro
  European Journal of Pharmacology, 891, 173684, 173684, Elsevier BV, 2021年01月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Hydrogen sulfide (H2S) has a variety of physiological functions. H2S reportedly increases intracellular Ca2+ concentration ([Ca2+]i) in astrocytes. However, the precise mechanism and functional role of this increase are not known. Here, we examined the effects of H2S on [Ca2+]i in astrocytes from the rat spinal cord and whether H2S affects ATP-induced Ca2+ signaling, which is known to be involved in synaptic function. Na2S (150 μM), an H2S donor, produced a nontoxic increase in [Ca2+]i. The [Ca2+]i increase by Na2S was inhibited by Ca2+ depletion in the endoplasmic reticulum (ER) but not by removal of extracellular Ca2+, indicating that H2S releases Ca2+ from the ER. On the other hand, Na2S inhibited ATP-induced [Ca2+]i increase when Na2S clearly increased [Ca2+]i in the astrocytes, which was not suppressed by a reducing agent. In addition, Na2S had no effect on intracellular cyclic AMP (cAMP) level. These results indicate that oxidative post-translational modification of proteins and cAMP are not involved in the inhibitory effect of H2S on ATP-induced Ca2+ signaling. We conclude that H2S indirectly inhibits ATP-induced Ca2+ signaling by decreasing Ca2+ content in the ER in astrocytes. In this way, H2S may influence intercellular communication between astrocytes and neurons, thereby contributing to neuronal signaling in the nervous system.
• Fibroblast growth factor 2 upregulates ecto-5′-nucleotidase and adenosine deaminase via MAPK pathways in cultured rat spinal cord astrocytes
  Ryota Eguchi; Taisuke Kitano; Ken-ichi Otsuguro
  Purinergic Signalling, 16, 4, 519, 527, Springer Science and Business Media LLC, 2020年12月, ［査読有り］, ［筆頭著者, 責任著者］
  英語, 研究論文（学術雑誌）, 13713135
• Bidirectional modulation of TNF-α transcription via α- and β-adrenoceptors in cultured astrocytes from rat spinal cord.
  Kohei Morimoto; Taisuke Kitano; Ryota Eguchi; Ken-Ichi Otsuguro
  Biochemical and biophysical research communications, 2020年05月22日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Noradrenaline (NA) suppresses TNF-α production via β-adrenoceptors (ARs) in brain astrocytes. However, the downstream pathways from β-ARs, and the involvement of α-ARs, remains unknown. In this study, we investigated the AR-mediated regulation of TNF-α mRNA levels in cultured astrocytes from rat spinal cord. NA, the α1-agonist phenylephrine, and the β-agonist isoproterenol decreased the TNF-α mRNA level, while the α2-agonist dexmedetomidine increased it. The isoproterenol-induced TNF-α mRNA decrease was accompanied by a decrease in ERK phosphorylation. An adenylyl cyclase activator and an ERK inhibitor mimicked these effects. These results indicate that the transcriptional regulation of TNF-α by β-ARs is mediated via cAMP pathways followed by the ERK pathway inhibition. The dexmedetomidine-induced TNF-α mRNA increase was accompanied by phosphorylation of JNK and ERK, which was blocked by a JNK inhibitor. Furthermore, the LPS-induced increase in the TNF-α mRNA level was accompanied by NF-κB nuclear translocation, and both these effects were blocked by phenylephrine. An NF-κB inhibitor suppressed the LPS-induced increase in the TNF-α mRNA level. These results suggest that α1-ARs suppress the LPS-induced increase in the TNF-α mRNA level via inhibition of NF-κB nuclear translocation. Taken together, our study reveals that both α- and β-ARs are involved in the transcriptional regulation of TNF-α in astrocytes.
• Fibroblast growth factor 2 modulates extracellular purine metabolism by upregulating ecto-5'-nucleotidase and adenosine deaminase in cultured rat spinal cord astrocytes.
  Eguchi R; Yamaguchi S; Otsuguro KI
  Journal of pharmacological sciences, 139, 2, 98, 104, 2019年02月, ［査読有り］, ［筆頭著者］
• IL-1β augments H₂S-induced increase in intracellular Ca²⁺ through polysulfides generated from H₂S/NO interaction.
  Ujike A; Kuraishi T; Yamaguchi S; Eguchi R; Kitano T; Kamise J; Ito S; Otsuguro KI
  European journal of pharmacology, 821, 88, 96, Elsevier B.V., 2018年02月15日, ［査読有り］
  英語, 研究論文（学術雑誌）
• Different mechanisms of extracellular adenosine accumulation by reduction of the external Ca2+ concentration and inhibition of adenosine metabolism in spinal astrocytes
  Ryota Eguchi; Sanae Akao; Ken-ichi Otsuguro; Soichiro Yamaguchi; Shigeo Ito
  JOURNAL OF PHARMACOLOGICAL SCIENCES, 128, 1, 47, 53, 2015年05月, ［査読有り］, ［筆頭著者］
  英語, 研究論文（学術雑誌）

• 生命科学特論, 2024年, 博士後期課程, 獣医学院
• 先端生命科学特論Ⅳ：薬理学, 2024年, 博士後期課程, 獣医学院
• 機能制御薬理学, 2024年, 学士課程, 獣医学部
• アドバンスト演習, 2024年, 学士課程, 獣医学部
• アドバンスト演習, 2024年, 学士課程, 獣医学部
• 薬理学実習, 2024年, 学士課程, 獣医学部
• 札幌基礎獣医学演習・獣医学概論, 2024年, 学士課程, 獣医学部

• 日本薬理学会
• 日本獣医学会

• グリア細胞連関によるプリン代謝・取込み制御メカニズムの解明
  科学研究費助成事業
  2024年04月 - 2027年03月
  江口 遼太
  日本学術振興会, 若手研究, 北海道大学, 研究代表者, 24K18038
• 抗うつ薬によるアストロサイトのプリン放出・代謝機能変化の解析
  研究活動スタート支援
  2019年10月 - 2021年03月
  江口 遼太
  日本学術振興会, 研究代表者, 競争的資金
• 虚血病態下におけるアストロサイトのプリン作動性機構
  科学研究費助成事業
  2016年04月22日 - 2019年03月31日
  江口 遼太
  中枢神経系の虚血病態下では、細胞外のアデノシン（ADO）が増加し神経保護作用を示す。細胞外のADO増加は、主に放出されたATPなどのプリン化合物が細胞外で代謝されて生じる。この反応にはアストロサイトが関与すると考えられているが、その機序には未だ不明な点が多い。本研究では、このADO増加機序の解明を目的としている。
  アストロサイトは病態下で形態や機能が変化することが知られている。虚血病態下でもこの状態変化により、ATP放出や細胞外のプリン化合物代謝が変化する可能性がある。前年度までの研究により、線維芽細胞成長因子2（FGF2）がアストロサイトからのATP放出や細胞外プリン代謝を促進することを明らかにした。そこでこれらの変化がどのような細胞内経路を介するのか検討した。まず、FGF受容体阻害薬はFGF2によるATP放出増加やプリン代謝酵素の発現と活性の上昇を抑制した。続いてFGF受容体下流経路の1つであるMAPK経路に属するMEK、p38、JNKの阻害薬を用いた。MEK阻害薬はFGF2によるATP放出増加やプリン代謝酵素の発現と活性の上昇を強く抑制したのに対し、p38阻害薬及びJNK阻害薬はプリン代謝酵素の発現・活性上昇を一部抑制した。これらの結果から、FGF2はFGF受容体やMAPK経路を介してアストロサイトのプリン放出・代謝促進を引き起こしていることが明らかになった。
  さらに本研究では、アストロサイトからプリン代謝酵素のADAが細胞外に放出され、その放出もFGF2により増加することを前年度までに示した。そのため、アストロサイトからのADA放出機序を検討した。細胞からのタンパク放出経路である開口放出、オートファジーやエクソソーム放出の阻害薬を用いたが、いずれも細胞外ADAの活性や発現に影響を与えなかった。放出経路の解明にはさらなる研究が必要である。
  日本学術振興会, 特別研究員奨励費, 北海道大学, 16J02751