Pathophysiological analysis of essential tremor and identification of the novel therapeutic targets.

• Project/Area Number: 16K21501
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy; General pharmacology
• Research Institution: Osaka University of Pharmaceutical Sciences
• Principal Investigator: Shimizu Saki 大阪薬科大学, 薬学部, 助教 (00630815)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 本態性振戦 / β遮断薬 / aspartoacylase / 脳内モノアミン / セロトニン（5-HT） / 下オリーブ核 / セロトニン代謝回転 / β受容体遮断薬 / Fosタンパク / 行動薬理学 / 動物モデル / 薬理学 / 神経科学 / 脳神経疾患

Outline of Final Research Achievements

To explore the novel therapeutics of essential tremor, we analyzed the pharmacological mechanism of non-selective β blocker, propranolol, the control therapy against essential tremor, using the spontaneous essential tremor model, Tremor rat. Propranolol inhibited the neural excitation of the inferior olive, the generation site of tremor, which it was the effect via the intracerebral β2 receptors. Also, both Tremor rat and aspartoacylase-KO rat showed enhancement of 5-HT turnover in the inferior olive. In addition, the deletion of aspartoacylase increased the sensitivity of tremor induction. The present study suggests that these targets may be useful for the novel therapeutics for essential tremor.

Academic Significance and Societal Importance of the Research Achievements

本態性振戦は高齢者に多く発症する不随意運動障害であり、認知症やパーキンソン病などとの合併症が多く認められる疾患である。手先の不自由を伴う微細運動障害は、患者のQOLに大きな障害となっている。しかし未だ根本的治療薬は存在せず、より有効性の高い新たな治療法の開発が求められてきた。本研究成果は、本態性振戦の発現機序や対症療法であるβ遮断薬の作用機序、脳内5-HT代謝回転と振戦発現との関連性の解明に繋がるものであり、本態性振戦の新規治療法開発における重要な知見が得られたものと考えられる。

Research Products

• [Journal Article] Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats. (2019)
  • Author(s): Masato Kinboshi , Saki Shimizu, Tomoji Mashimo, Tadao Serikawa, Hidefumi Ito, Akio Ikeda, Ryosuke Takahashi, Yukihiro Ohno
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 5 Pages: 001-015
  • DOI: 10.3390/ijms20051013
  • Peer Reviewed / Open Access
• [Journal Article] Mechanism Underlying Organophosphate Paraoxon-Induced Kinetic Tremor. (2019)
  • Author(s): Iha HA, Kunisawa N, Shimizu S, Onishi M, Nomura Y, Matsubara N, Iwai C, Ogawa M, Hashimura M, Sato K, Kato M, Ohno Y.
  • Journal Title: Neurotox Res. Volume: 35 Issue: 3 Pages: 575-583
  • DOI: 10.1007/s12640-019-0007-7
  • Peer Reviewed
• [Journal Article] Inwardly rectifying potassium channel Kir4.1 as a novel modulator of BDNF expression in astrocytes. (2018)
  • Author(s): Y. Ohno, M. Kinboshi, S. Shimizu
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 11 Pages: 3313-3313
  • DOI: 10.3390/ijms19113313
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological characterization of nicotine-induced tremor: Responses to anti-tremor and anti-epileptic agents. (2018)
  • Author(s): N. Kunisawa, S. Shimizu, M. Kato, H. A. Iha, C. Iwai, M. Hashimura, M. Ogawa, S. Kawaji, K. Kawakita, K. Abe, Y. Ohno
  • Journal Title: Journal of Pharmacological Sciences Volume: 137 Issue: 2 Pages: 162-169
  • DOI: 10.1016/j.jphs.2018.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway (2017)
  • Author(s): Saki Shimizu、Shunsaku Sogabe、Ryoto Yanagisako、Akiyoshi Inada、Megumi Yamanaka、Higor Iha、Yukihiro Ohno
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 7 Pages: 1416-1416
  • DOI: 10.3390/ijms18071416
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes (2017)
  • Author(s): Kinboshi Masato、Mukai Takahiro、Nagao Yuki、Matsuba Yusuke、Tsuji Yoshimi、Tanaka Shiho、Tokudome Kentaro、Shimizu Saki、Ito Hidefumi、Ikeda Akio、Inanobe Atsushi、Kurachi Yoshihisa、Inoue Seiji、Ohno Yukihiro
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 10 Pages: 408-408
  • DOI: 10.3389/fnmol.2017.00408
  • Peer Reviewed / Open Access
• [Journal Article] Serotonergic modulation of nicotine-induced kinetic tremor in mice (2017)
  • Author(s): Kunisawa Naofumi、Iha Higor A.、Nomura Yuji、Onishi Misaki、Matsubara Nami、Shimizu Saki、Ohno Yukihiro
  • Journal Title: Journal of Pharmacological Sciences Volume: 134 Issue: 2 Pages: 131-138
  • DOI: 10.1016/j.jphs.2017.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Tremor dominant Kyoto ( Trdk ) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca 2+ -activated K + channel (2017)
  • Author(s): Kuramoto Takashi、Yokoe Mayuko、Kunisawa Naofumi、Ohashi Kana、Miyake Takahito、Higuchi Yuki、Yoshimi Kazuto、Mashimo Tomoji、Tanaka Miyuu、Kuwamura Mitusru、Kaneko Shuji、Shimizu Saki、Serikawa Tadao、Ohno Yukihiro
  • Journal Title: Brain Research Volume: 1676 Pages: 38-45
  • DOI: 10.1016/j.brainres.2017.09.012
  • Peer Reviewed / Open Access
• [Journal Article] Nicotine elicits convulsive seizures by activating amygdalar neurons. (2017)
  • Author(s): Iha HA, Kunisawa N, Shimizu S, Tokudome K, Mukai T, Kinboshi M, Ikeda A, Ito H, Serikawa T, Ohno Y
  • Journal Title: Frontiers in Pharmacology Volume: 8 Pages: 57-57
  • DOI: 10.3389/fphar.2017.00057
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetylcholine receptors. (2016)
  • Author(s): N. Kunisawa, H. A. Iha, S. Shimizu, K. Tokudome, T. Mukai, M. Kinboshi, T. Serikawa, Y. Ohno: Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetyl
  • Journal Title: Behav. Brain Res. Volume: 314 Pages: 173-180
  • DOI: 10.1016/j.bbr.2016.08.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunohistochemical analysis of Fos protein expression for exploring brain regions related to central nervous system disorders and drug actions. (2016)
  • Author(s): H.A. Iha, N. Kunisawa, K. Tokudome, T. Mukai, M. Kinboshi, S. Shimizu, Y. Ohno
  • Journal Title: Neuromethods Volume: 121 Pages: 389-408
  • DOI: 10.1007/978-1-4939-6490-1_17
  • ISBN: 9781493964888, 9781493964901
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of aspartoacylase in tremor expression in rats (2016)
  • Author(s): A. Nishitani, M. Tanaka, S. Shimizu, N. Kunisawa, M. Yokoe, Y. Yoshida, T. Suzuki, T. Sakuma, T. Yamamoto, M. Kuwamura, S. Takenaka, Y. Ohno, T. Kuramoto
  • Journal Title: Experimental Animals Volume: 65 Issue: 3 Pages: 293-301
  • DOI: 10.1538/expanim.16-0007
  • NAID: 130006882372
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Presentation] アスパルトアシラーゼ遺伝子欠損ラットにおける下オリーブ核のセロトニン合成および代謝回転の亢進作用 (2019)
  • Author(s): 清水佐紀、升田晋一朗、尾来雪絵、勝見菜奈、阿部圭佑、西谷あい、庫本高志、大野行弘
  • Organizer: 日本薬学会第139年会
• [Presentation] Enhancement of 5-HT synthesis and metabolism in aspartoacylase-knockout rats. (2019)
  • Author(s): Kasumi Maekawa, Saki Shimizu, Shinichiro Masuda, Yukie Oguru, Nana Katsumi, Keisuke Abe, Ai Nishitani, Takashi Kuramoto, Yukihiro Ohno
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Mechanism of organophosphate paraoxon-induced kinetic tremor in mice. (2019)
  • Author(s): Yukihiro Ohno, Chihiro Iwai, Iha Higor. A, Naofumi Kunisawa, Saki Shimizu, Masaki Kato, Mizuki Ogawa, Mai Hashimura
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Aspartoacylase遺伝子欠損ラットにおける脳内モノアミン含量の解析 (2018)
  • Author(s): 升田晋一朗、阿部圭佑、尾来雪絵、勝見菜奈、清水佐紀、大野行弘
  • Organizer: 第68回日本薬学会近畿支部総会・大会
• [Presentation] ニコチン誘発振戦の薬理解析：抗振戦薬および抗てんかん薬に対する反応性評価 (2018)
  • Author(s): 加藤将貴、國澤直史、清水佐紀、Higor Alves Iha、岩井千紘、橋村 舞、小川瑞葵、川路翔平、河北和馬、阿部圭佑、大野行弘
  • Organizer: 第133回日本薬理学会近畿部会
• [Presentation] 抗精神病薬による錐体外路障害の発現予測とセロトニン神経に着目した回避法検討 (2018)
  • Author(s): 清水佐紀、多田羅絢加、水口裕登、安達咲希、木津朋也、祖父江顕、藤原麻衣、森本朋樹、大野行弘
  • Organizer: 生体機能と創薬シンポジウム2018
• [Presentation] ニコチン誘発振戦の薬理解析：抗振戦薬および抗てんかん薬に対する反応性評価 (2018)
  • Author(s): 加藤将貴、國澤直史、清水佐紀、岩井千紘、小川瑞葵、橋村舞、河合悦子、大野行弘
  • Organizer: 日本薬学会第138年会
• [Presentation] Effects of D-cycloserine, a glycine-binding site agonist of NMDA receptors, on antipsychotic-induced extrapyramidal side effects. (2017)
  • Author(s): Saki Shimizu, Tomohiro Sekiguchi, Nanami Ikeda, Saya Okamura, Saki Itaya, Yukihiro Ohno
  • Organizer: 第90回日本薬理学会総会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] パラオキソンによる振戦発現のメカニズム解析 (2017)
  • Author(s): 國澤直史、Higor A. Iha、清水佐紀、尾西美咲、野村有治、松原菜美、岩井千紘、小川瑞葵、橋村舞、河合悦子、大野行弘
  • Organizer: 第44回日本毒性学会学術集会
• [Presentation] Glycine-binding site agonists of NMDA receptors alleviate extrapyramidal side effects by activating nigrostriatal dopamine pathway. (2017)
  • Author(s): Saki Shimizu, Shunsaku Sogabe, Ryoto Yanagisako, Akiyoshi Inada, Megumi Yamanaka, Yukihiro Ohno
  • Organizer: 第40回日本神経科学大会
• [Presentation] Serotonergic modulation of nicotine-induced tremor. (2017)
  • Author(s): Naofumi Kunisawa, Higor A. Iha, Misaki Onishi, Yuji Nomura, Nami Matsubara, Saki Shimizu, Yukihiro Ohno
  • Organizer: 第40回日本神経科学大会
• [Presentation] NMDA受容体グリシン結合部位活性化薬は黒質－線条体ドパミン神経路の活性化を介して錐体外路障害を改善する (2017)
  • Author(s): 清水佐紀、曽我部俊策、柳迫領仁、稲田顕慶、山中萌、大野行弘
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
• [Presentation] ニコチン誘発振戦に対するセロトニン神経系の調節メカニズム (2017)
  • Author(s): 國澤直史、Higor A. Iha、清水佐紀、大野行弘
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] SK2チャネル遺伝子にミスセンス変異を持つ振戦ラット (2017)
  • Author(s): 庫本高志、横江繭子、国澤直史、大橋佳奈、三宅崇仁、樋口裕城、吉見一人、真下知二、田中美有、桑村 充、金子周二、清水佐紀、芹川忠夫、大野行弘
  • Organizer: 第136回関西実験動物研究会
• [Presentation] Evaluation of the extrapyramidal side effects (EPS) liability of NMDA receptor glycine-binding site agonists. (2016)
  • Author(s): Yukihiro Ohno, Yuka Sato, Syodai Fujii, Ryo Wakamatsu, Haruna Takasaki, Megumi Yamanaka, Akiyoshi Inada, Syunsaku Sogabe, Ryoto Yanagisako, Saki Shimizu
  • Organizer: 30th CINP World congress of Neuropsychopharmacology
  • Place of Presentation: Korea (Seoul)
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] Nicotine evokes convulsive seizures by activating amygdala neurons partly through α7nACh receptors. (2016)
  • Author(s): Higor A. Iha, Naofumi Kunisawa, Saki Shimizu, Yuto Mizuguchi, Takanori Nohara, Yudai Atsuta, Keito Yoshikawa, Kentaro Tokudome, Masato Kinboshi, Tadao Serikawa, Yukihiro Ohno
  • Organizer: 30th CINP World congress of Neuropsychopharmacology
  • Place of Presentation: Korea (Seoul)
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] Pharmacological analysis of nicotine-induced tremor. (2016)
  • Author(s): Naofumi Kunisawa, Higor A. Iha, Saki Shimizu, Yudai Atsuta, Takanori Nohara, Kento Yoshikawa, Kentaro Tokudome, Yukihiro Ohno
  • Organizer: 30th CINP World congress of Neuropsychopharmacology
  • Place of Presentation: Korea (Seoul)
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] Analysis of causative brain regions for nicotine-induced seizures. (2016)
  • Author(s): Naofumi Kunisawa, Higor A. Iha, Saki Shimizu, Yuto Mizuguchi, Takanori Nohara, Yudai Atsuta, Keito Yoshikawa, Kentaro Tokudome, Masato Kinboshi, Tadao Serikawa, Yukihiro Ohno
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: 韓国（ソウル）
  • Year and Date: 2016-07-02
• [Presentation] Pharmacological responses of nicotine-induced tremor to various anti-tremor agents. (2016)
  • Author(s): Higor A. Iha, Naofumi Kunisawa, Saki Shimizu, Yudai Atsuta, Takanori Nohara, Kento Yoshikawa, Kentaro Tokudome, Yukihiro Ohno
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: 韓国（ソウル）
  • Year and Date: 2016-07-02
• [Presentation] ニコチンによる運動興奮症状の発現メカニズム解析 (2016)
  • Author(s): 國澤直史、Higor A. Iha、清水佐紀、尾西美咲、野村有治、松原菜美、徳留健太郎、河合悦子、大野行弘
  • Organizer: 第66回日本薬学会近畿支部総会
  • Place of Presentation: 大阪
• [Presentation] NMDA受容体グリシン結合部位活性化薬の線条体内ドパミン遊離に対する影響 (2016)
  • Author(s): 関口知弘、池田菜々美、板谷紗希、岡村沙耶、秋葉健太、藤井 恵、山本真奈、清水佐紀、大野行弘
  • Organizer: 第66回日本薬学会近畿支部総会
  • Place of Presentation: 大阪
• [Presentation] ニコチン誘発振戦におけるセロトニン受容体の関与 (2016)
  • Author(s): 野村有治、尾西美咲、松原菜美、國澤直史、Higor A. Iha、清水佐紀、河合悦子、大野行弘
  • Organizer: 第66回日本薬学会近畿支部総会
  • Place of Presentation: 大阪
• [Presentation] Acute nicotine causes convulsive seizures by activating amygdala neurons, primarily through α7nACh receptors. (2016)
  • Author(s): Higor A. Iha、國澤直史、清水佐紀、熱田侑大、野原孝紀、吉川健斗、徳留健太郎、大野行弘
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都