Analysis of glial-neuronal network abnormalities in treatment-resistant schizophrenia

• Project/Area Number: 15H04894
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Shimane University
• Principal Investigator: Miyaoka Tsuyoshi 島根大学, 学術研究院医学・看護学系, 准教授 (50284047)
• Co-Investigator(Kenkyū-buntansha): 橋岡 禎征 島根大学, 学術研究院医学・看護学系, 講師 (00622523) ; 津森 登志子 県立広島大学, 保健福祉学部(三原キャンパス), 教授 (30217377)
• Research Collaborator: TSUCHIE keiko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: 統合失調症 / グリア細胞 / ヒト死後脳 / 免疫組織染色 / 精神生理学 / 神経細胞

Outline of Final Research Achievements

We are investigating the relationship between glial activation and schizophrenia. In this study, we investigated the postmortem expression of glial cells in the hippocampal region of brains of patients with schizophrenia using an immunofluorescence technique. As a result, although difficult in many cases, we successfully detected immunoreactivities for Iba-1 and S100-β in the dentate gyrus in the postmortem brains.
In addition, we compared the sensitivity of the NMDA-antagonist, ketamine to validate the Gunn rat as a schizophrenia model. By inducing ketamine, Gunn rats exhibited acute hyperactivity and PPI deficits which are positive and negative symptoms respectively of schizophrenia.
Despite its limitations, efforts to document immunohistochemical glial expressions in postmortem brains will provide possible in situ information for the various approaches to using animal models for patients with schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

これまでの統合失調症の治療薬はドパミン仮説に基づいて開発されたドパミン受容体遮断薬が主流であるが、治療抵抗性統合失調症にグリア－ニューロン回路網の変化が関与していること（神経炎症仮説）をヒト死後脳で解明する試みは他に例がない。本研究により治療抵抗性統合失調症の治療戦略として「神経炎症を鎮静する」物質を探索することの重要性が高まると同時に、我々が提唱する塩酸ミノサイクリン療法が統合失調症の根治治療薬として位置づけられる可能性も高くなり、学術的にも社会的にも意義深い研究であると考えられる。

Research Products

• [Journal Article] Salivary Alpha-Amylase Activity Levels in Catatonic Schizophrenia Decrease after Electroconvulsive Therapy (2018)
  • Author(s): Kanayama Misako、Miyaoka Tsuyoshi、Araki Tomoko、Hayashida Maiko、Hashioka Sadayuki、Horiguchi Jun
  • Journal Title: Case Reports in Psychiatry Volume: 2018 Pages: 1-5
  • DOI: 10.1155/2018/2623585
  • NAID: 120006733315
  • Peer Reviewed
• [Journal Article] Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test (2018)
  • Author(s): Arauchi Ryosuke、Hashioka Sadayuki、Tsuchie Keiko、Miyaoka Tsuyoshi、Tsumori Toshiko、et.al.
  • Journal Title: Brain and Behavior Volume: 8 Issue: 8
  • DOI: 10.1002/brb3.1028
  • NAID: 120006733314
  • Peer Reviewed
• [Journal Article] Remission of Psychosis in Treatment-Resistant Schizophrenia Transplantation: A Case Report. (2017)
  • Author(s): Tsuyoshi Miyaoka, Rei Wake, Sadayuki Hashioka, Maiko Hayashida, Arata Oh-Nishi, Ilhamuddin Abdul Azis, Muneto Izuhara, Keiko Tsuchie, Tomoko Araki, Ryosuke Arauchi, Rostia Arianna Abdullah, Jun Horiguchi
  • Journal Title: Frontiers in Psychiatry Volume: ８ Pages: 174-174
  • DOI: 10.3389/fpsyt.2017.00174
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics analysis implies noninvolvement of the kynurenine pathway neurotoxins in the interferon-γ-induced neurotoxicity of adult human astrocytes. (2017)
  • Author(s): Sadayuki Hashioka, Hideyuki Suzuki, Daisuke Nakajima, Tsuyoshi Miyaoka, Rei Wake, Maiko Hayashida, Jun Horiguchi, Andis Klegeris
  • Journal Title: Neuropsychiatry Volume: 7(2) Pages: 156-163
  • Peer Reviewed / Open Access
• [Journal Article] Increase in Salivary Alpha-Amylase Levels among Non-Attending Junior High School Students Diagnosed with Social Anxiety Disorder. (2017)
  • Author(s): Takuji Inagaki, Michiharu Nagahama, Kiminori Kawano, Rei Wake, Tsuyoshi Miyaoka, Jun Horiguchi
  • Journal Title: Journal of Behavioral and Brain Science Volume: 7(8) Pages: 360-369
  • NAID: 120006537042
  • Peer Reviewed / Open Access
• [Journal Article] Long-term effects of combined treatment with memantine and donepezil on Alzheimer's disease patients: 72-week study (2017)
  • Author(s): Rei Wake, Tomoko Araki, Tsuyoshi Miyaoka, Michiharu Nagahama, Motohide Furuya, Maiko Hayashida, Sadayuki Hashioka, Jun Horiguch
  • Journal Title: Neuropsychiatry Volume: 8(1) Pages: 739-744
  • Peer Reviewed / Open Access
• [Journal Article] Effects of yokukansan, a Japanese kampo medicine, for symptoms associated autism spectrum disorder. (2016)
  • Author(s): Wake R, Miyaoka T, Furuya M, Hashioka S, Horiguchi J
  • Journal Title: CNS and Neurological Dosorders-Drug Targets Volume: 15(5) Pages: 551-563
  • Peer Reviewed / Open Access
• [Journal Article] A long-term study of the association between the relative poverty rate and suicide rate in Japan. (2016)
  • Author(s): Inoue, K, Fujita, Y, Takeshita, H, Abe, S, Fujihara, J, Ezoe, S, Sampei, M, Miyaoka, T, Horiguchi, J, Okazaki, Y, Fukunaga, T
  • Journal Title: J Forensic Sci Volume: 61 Issue: S1 Pages: 268-281
  • DOI: 10.1111/1556-4029.12998
  • Peer Reviewed / Open Access
• [Journal Article] Aceruloplasminemia With Psychomotor Excitement and Neurological Sign Was Improved by Minocycline. (2016)
  • Author(s): Hayashida M, Hashioka S, Miki H, Nagahama M, Wake R, Miyaoka T, Horiguchi J
  • Journal Title: Medicine Volume: 95(19) Issue: 19 Pages: 3594-3594
  • DOI: 10.1097/md.0000000000003594
  • Peer Reviewed / Open Access
• [Journal Article] Epidemiological Characteristics of Disaster-related Suicides in the 3-4 Years since the Great East Japan Earthquake. (2016)
  • Author(s): Ken Inoue, Haruo Takeshita, Yoshikazu Takinami, Masaharu Hoshi, Yoshihiro Noso, Nobuo Takeichi, Junko Fujihara, Kaori Kimura-Kataoka, Yasuyuki Fujita, Rei Wake, Tsuyoshi Miyaoka, Satoko Ezoe, Jun Horiguchi, Yuji Okazaki
  • Journal Title: International Journal of Emergency Mental Health and Human Resilience Volume: 18(2) Pages: 742-743
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics analysis implies noninvolvement of the kynurenine pathway neurotoxins in the interferon-γ-induced neurotoxicity of adult human astrocytes. (2016)
  • Author(s): Hashioka S, Suzuki H, Nakajima D, Miyaoka T, Wake R, Hayashida M, Horiguchi J, Klegeris A
  • Journal Title: Neuropsychiatry Volume: 7(1) Pages: 610-617
  • Peer Reviewed / Open Access
• [Journal Article] Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat. (2016)
  • Author(s): Limoa E, Hashioka S, Miyaoka T, Tsuchie K, Arauchi R, Azis A I, Wake R, Hayashida M, Araki T, Furuya M, Liaury K, Tanra A J, Horiguchi J
  • Journal Title: Journal of Neuroinflammation Volume: 13(1) Issue: 1 Pages: 230-230
  • DOI: 10.1186/s12974-016-0688-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 生活臨床的介入により早期に寛解に至った統合失調症の1例. (2016)
  • Author(s): 金山三紗子, 宮岡剛, 堀口淳
  • Journal Title: 精神科 Volume: 29(6) Pages: 519-523
  • NAID: 40021016780
  • Peer Reviewed / Open Access
• [Journal Article] Regional Cerebral blood flow in late-onset schizophrenia:a SPECT study using 99mTc-ECD. (2015)
  • Author(s): Wake R, Miyaoka T, Araki T, Kawakami K, Furuya M, Limoa E, Hashioka S, Horiguchi J
  • Journal Title: European Archives of Psychiatry and Clinical Neuroscience. Volume: 10 Issue: 1 Pages: 11-11
  • DOI: 10.1007/s00406-015-0607-z
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of Sansoninto in Insomnia with Psychiatric Disorder: An Open-Label Study. (2015)
  • Author(s): Tsuyoshi Miyaoka, Kiminori Kawano, Motohide Furuya, Rei Wake, Sadayuki Hashioka, Kristian Liaury, Erlyn Limoa, Keiko Tsuchie, Michiyo Fukushima, Tomoko Araki, Jun Horiguchi
  • Journal Title: Journal Alternative & Integrative Medicine Volume: 4(1) Issue: 01 Pages: 6-6
  • DOI: 10.4172/2327-5162.1000181
  • Peer Reviewed / Open Access
• [Journal Article] Ramelteon as adjunctive therapy for delirium referred to a consultation-liaison psychiatry service:a retrospective analysis. (2015)
  • Author(s): Furuya M, Miyaoka T, Yasuda H, Wake R, Hashioka S, Miura S, Nagahama M, Araki T, Horiguchi J
  • Journal Title: International Journal of Geriatric Psychiatry Volume: 30 Pages: 994-997
  • Peer Reviewed
• [Journal Article] Efficacy and safety yokukansan in treatment-resistant schizophrenia:a randomized,double-blind, placebo-controlled trial( a Positive and Negative Syndrome Scale,five-factor analysis). (2015)
  • Author(s): Miyaoka T, Furuya M, Horiguchi J, Wake R, Hashioka S, Tohyama M, Mori N, Minabe Y, Iyo M, Ueno S, Ezoe S, Murotani K, Hoshino S, Seno H
  • Journal Title: Psychopharmacology Volume: 232(1) Pages: 155-164
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 精神疾患の睡眠障害に対する酸棗仁湯の効果. (2015)
  • Author(s): 宮岡剛
  • Journal Title: 漢方と最新治療 Volume: 24(1) Pages: 23-26
  • Peer Reviewed
• [Journal Article] Analysis of oxidative stress expressed by urinary level of biopyrrins and 8-hydroxydeoxyguanosine in patients with chronic schizophrenia. (2015)
  • Author(s): Miyaoka T, Ieda M, Hashioka S, Wake R, Furuya M, Liaury K, Hayashida M, Tsuchie K, Arauchi R, Araki T, Shioji I, Ezoe S, Inoue K, Yamaguchi T, Horiguchi J
  • Journal Title: Psychiatry Clin Neurosci Volume: 69(11) Issue: 11 Pages: 693-698
  • DOI: 10.1111/pcn.12319
  • Peer Reviewed / Open Access
• [Journal Article] パーソナリティ障害と漢方-境界性パーソナリティ障害に対する抑肝散の効果- (2015)
  • Author(s): 宮岡剛
  • Journal Title: 精神科 Volume: 27(3) Pages: 170-174
  • Peer Reviewed
• [Journal Article] 治療抵抗性統合失調症に対する抑肝散の有用性に関する臨床研究. (2015)
  • Author(s): 宮岡剛
  • Journal Title: 脳21 Volume: 18(4) Pages: 242-248
  • Peer Reviewed
• [Presentation] 統合失調症前駆期でのバイオマーカーによる酸化ストレス状態の把握と早期診断の可能性. (2018)
  • Author(s): 和氣玲, 荒木智子, 稲垣卓司, 土江景子, 林田麻衣子, 橋岡禎征, 堀口淳, 大西新, 宮岡剛
  • Organizer: 第114回日本精神神経学会学術総会
• [Presentation] Postmortem expression of Iba1 and S100β immunoreactivities in the hippocampal dentate gyrusb in patients with schizophrenia. (2018)
  • Author(s): Keiko Tsuchie, Toshiko Tsumori, Sadayuki Hashioka, Tsuyoshi Miyaoka
  • Organizer: 第41回日本神経科学大会
• [Presentation] 統合失調症の層別化と根治療法の創出を目指した研究. (2018)
  • Author(s): 宮岡 剛
  • Organizer: 第3回黒潮カンファレンス
• [Presentation] mECTの治療効果と唾液アミラーゼ値の推移が一致した緊張型統合失調症の2症例. (2017)
  • Author(s): 金山三紗子, 宮岡剛, 家田麻紗, 稲垣卓司, 小池昌弘, 松田泰行, 三木啓之, 三浦章子, 田中一平, 山下智子, 長濱道治, 大朏孝治, 林田麻衣子, 和氣玲, 橋岡禎征, 堀口淳
  • Organizer: 第13回日本統合失調症学会
• [Presentation] 統合失調症の前駆期に対する治療的介入により心拍数変動の変化を認めた2症例. (2017)
  • Author(s): 和氣玲, 宮岡剛, 荒木智子, 古屋智英, 橋岡禎征, 堀口淳
  • Organizer: 第13回日本統合失調症学会
• [Presentation] Schizophrenia and Idiopathic Unconjugated Hyperbilirubinemia(Gilbert's Syndrome). (2017)
  • Author(s): Tsuyoshi Miyaoka
  • Organizer: The 5th Congress of AsCNP.
  • Int'l Joint Research / Invited
• [Presentation] Electroconvulsive shock affected the schizophrenia-like behavior and the glial activation in the hippocampus of Gunn rat (2017)
  • Author(s): Erlyn Limoa, Sadayuki Hashioka, Tsuyoshi Miyaoka, Keiko Tsuchie, Ryosuke Arauchi, Rei Wake, Maiko Hayashida, Tomoko Araki, Motohide Furuya, Ilhamuddin, Kristian Liaury, Andi Jayalangkara Tanra, Jun Horiguchi
  • Organizer: The 5th Congress of AsCNP
  • Int'l Joint Research
• [Presentation] 児童思春期の自閉症スペクトラム障害における精神症状に抑肝散が効果的であった 4 症例. (2017)
  • Author(s): 和気玲, 宮岡剛, 稲垣卓司, 古屋 智英, 橋岡 禎征, 堀口 淳
  • Organizer: 第113回日本精神神経学会学術総会.
• [Presentation] 児童思春期における不眠に対する酸棗仁湯の有効性. (2017)
  • Author(s): 宮岡剛, 河野公範, 古屋智英, 和氣玲, 橋岡禎征, 堀口淳
  • Organizer: 第113回日本精神神経学会学術総会
• [Presentation] 右前大脳動脈低形成を伴う注意欠陥多動性障害の2症例. (2017)
  • Author(s): 和氣玲, 宮岡剛, 松田泰行, 荒木智子, 長濱道治, 林田麻衣子, 橋岡禎征, 堀口淳
  • Organizer: 第22回日本神経精神医学会
• [Presentation] 鉄代謝異常症の経験からミノサイクリンの有効性についての検討. (2017)
  • Author(s): 林田麻衣子, 宮岡剛, 伊豆原宗人, 小池昌弘, 松田泰行, 三木啓之, 金山三紗子, 三浦章子, 山下智子, 河野公範, 長濱道治, 岡崎四方, 橋岡禎征, 和氣玲, 堀口淳
  • Organizer: 第27回日本臨床精神神経薬理学会
• [Presentation] 気分障害が先行した前頭側頭型認知症の三症例. (2016)
  • Author(s): 三浦章子, 長濱道治, 三木啓之, 田中一平, 金山三紗子, 山下智子, 林田麻衣子, 和氣玲, 橋岡禎征, 宮岡剛, 堀口淳
  • Organizer: 第57回中国・四国精神神経学会.
  • Place of Presentation: 松山市（メルパルク松山）
  • Year and Date: 2016-11-10
• [Presentation] 修正型電気けいれん療法とクロザピンにより衝動性と問題行動が改善した解体型統合失調症の1例. (2016)
  • Author(s): 松田泰行, 長濱道治, 林田麻衣子, 和氣玲, 橋岡禎征, 宮岡剛, 堀口淳
  • Organizer: 第57回中国・四国精神神経学会.
  • Place of Presentation: 松山市（メルパルク松山）
  • Year and Date: 2016-11-10
• [Presentation] Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and improved schizophrenia-like behavior of Gunn Rat. (2016)
  • Author(s): LIMOA ERLYN, 橋岡禎征, 宮岡剛, 土江景子, 荒内亮輔, ABDUL AZIS ILHAMUDDIN, 和氣玲, 林田麻衣子, 荒木智子, 古屋智英, LIAURY KRISTIAN, TANRA ANDI JAYALANGKARA, 堀口淳
  • Organizer: 第57回中国・四国精神神経学会.
  • Place of Presentation: 松山市（メルパルク松山）
  • Year and Date: 2016-11-10
• [Presentation] 光トポグラフィー検査における陰転化波形に関する検討 (2016)
  • Author(s): 荒木智子, 和氣玲, 宮岡剛, 三浦章子, 田中一平, 長濱道治, 古屋智英, 岡崎四方, 橋岡禎征, 堀口淳
  • Organizer: 第36回日本精神科診断学会.
  • Place of Presentation: 東京都（順天堂大学）
  • Year and Date: 2016-08-05
• [Presentation] 意欲低下に対して釣藤散が有用と思われた軽度認知障害の1症例. (2016)
  • Author(s): 長濱道治, 小池昌弘, 松田泰行, 三木啓之, 田中一平, 三浦章子, 金山三紗子, 山下智子, 河野公範, 林田麻衣子, 岡崎四方, 和氣玲, 橋岡禎征, 宮岡剛, 堀口淳
  • Organizer: 第31回日本老年精神医学会.
  • Place of Presentation: 金沢市（金沢歌劇座）
  • Year and Date: 2016-06-23
• [Presentation] Analysis of urinary oxidative stress in patients with chronic schizophrenia. (2016)
  • Author(s): Miyaoka T, Wake R, Furuya M, Hayashida M, Nagahama M, Hashioka S, Horiguchi J
  • Organizer: 第112回日本精神神経学会学術総会.
  • Place of Presentation: 千葉市（幕張メッセ）
  • Year and Date: 2016-06-02
• [Presentation] アルツハイマー型認知症患者に対するガランタミンの効果 (2016)
  • Author(s): 和氣玲, 荒木智子, 宮岡剛, 古屋智英, 長濱道治, 林田麻衣子, 橋岡禎征, 堀口淳:
  • Organizer: 第112回日本精神神経学会学術総会.
  • Place of Presentation: 千葉市（幕張メッセ）
  • Year and Date: 2016-06-02
• [Presentation] アルツハイマー型認知症患者に対するガランタミンの効果と脳血流との関連 (2015)
  • Author(s): 和氣玲, 荒木智子, 宮岡剛, 長濱道治, Limoa E, 橋岡禎征, 堀口淳
  • Organizer: 第56回中国・四国精神神経学会
  • Place of Presentation: 倉敷市（倉敷市芸文館）
  • Year and Date: 2015-11-12
• [Presentation] Electroconvulsive shock altered schizophrenia-like behavior and glial activation in Gunn Rat. (2015)
  • Author(s): Limoa E, 橋岡禎征, 宮岡剛, 土江景子, 荒内亮輔, 和氣玲, 林田麻衣子, 荒木智子, Tanra Andi Jayalangka, 堀口淳
  • Organizer: 第42回日本脳科学会
  • Place of Presentation: 宮崎市（ＡＮＡホリディインリゾート宮崎)
  • Year and Date: 2015-11-12
• [Presentation] Effectiveness of Minocycline treatment in an Aceluroplasminemia Patient with Psychomotor Exitement neurological symptoms. (2015)
  • Author(s): Hayashida M, Miki H, Yasuda H, Miura S, Tanaka I, Nagahama M, Okazaki S, Wake R, Hashioka S, Miyaoka T, Horiguchi J
  • Organizer: The 9th International Congress of the Asian Society Against Dementia.
  • Place of Presentation: 熊本市（KKR HOTEL KUMAMOTO)
  • Year and Date: 2015-09-14
  • Int'l Joint Research
• [Presentation] 遅発性統合失調症におけるSPECTを用いた脳血流の変化. (2015)
  • Author(s): 和氣玲, 宮岡剛, 荒木智子, 古屋智英, 橋岡禎征, 堀口淳
  • Organizer: WPA REGIONAL CONGRESS OSAKA Japan2015
  • Place of Presentation: 大阪市（大阪国際会議場）
  • Year and Date: 2015-06-04
  • Int'l Joint Research
• [Presentation] 統合失調症の予防と治癒～体質性黄疸を合併する緊張型統合失調症に関する検討をもとに～ (2015)
  • Author(s): 宮岡剛
  • Organizer: WPA REGIONAL CONGRESS OSAKA Japan2015
  • Place of Presentation: 大阪市（大阪国際会議場）
  • Year and Date: 2015-06-04
  • Int'l Joint Research