Study on the improvements of the damaged brain networks in refractory depression.

• Project/Area Number: 26461723
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Sapporo Medical University
• Principal Investigator: Hashimoto Eri 札幌医科大学, 医学部, 准教授 (30301401)
• Co-Investigator(Kenkyū-buntansha): 山田 美佐 国立研究開発法人国立精神・神経医療研究センター, 精神保健研究所 精神薬理研究部, 科研費研究員 (10384182) ; 鵜飼 渉 札幌医科大学, 医療人育成センター, 准教授 (40381256)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 神経科学 / 脳・神経 / 精神疾患 / うつ病 / 抗うつ薬 / BDNF / アルコール / 難治性うつ病 / 神経新生 / 神経幹細胞

Outline of Final Research Achievements

We produced depressive model rats by exposure of chronic corticosterone treatment and refractory depression model rats by alcohol exposure during the fetal period followed by the corticosterone treatment during adolescent. Treatment with escitalopram reversed depression-like behavior in refractory depression model accompanied by the reduction of BDNF levels in serum. We analyzed the influence of alcohol drinking on the therapeutic effects of antidepressants and evaluated that co-occurrence of major depressive disorder and alcohol use disorder is associated with a lower response to antidepressant treatment. We also investigated the effect of Lysophosphatidic acid (LPA) on the viability of rat C6 glioma cells and found that an LPA receptor antagonist, BrP-LPA, competitively blocked the LPA-induced reduction of C6 cell viability through LPA receptors. These findings support the hypothesis that LPA plays important roles in astrocyte-mediated brain network impairment.

Research Products

• [Journal Article] アルコール性障害が関与する難治性うつ病の病態基盤－血中・脳中BDNF値の変動解析から－ (2016)
  • Author(s): 古瀬研吾，木川昌康，辻野華子，石井貴男，田山真矢，鵜飼渉，橋本恵理，齋藤利和, 河西千秋．
  • Journal Title: アルコールと医生物 Volume: 34 Pages: 29-30
• [Journal Article] 出生前のアルコール曝露 (2016)
  • Author(s): 木川昌康, 橋本恵理
  • Journal Title: 臨床精神医学 Volume: 45 Pages: 309-313
• [Journal Article] Stem cell therapy, a new approach to the treatment of refractory depression. (2015)
  • Author(s): Hashimoto E, Tayama M, Ishikawa H, Yamamoto M, Saito T.
  • Journal Title: J Neural Transm Volume: 122 Issue: 2 Pages: 301-306
  • DOI: 10.1007/s00702-014-1254-7
  • Peer Reviewed
• [Journal Article] 胎児期アルコール暴露と成長後のストレスを組み合わせた難治性うつ病モデルにおける神経幹細胞移植療法の有用性 (2015)
  • Author(s): 鵜飼渉, 木川昌康, 石井貴男, 古瀬研吾, 辻野華子, 岩本倫, 田山真矢, 白石将毅, 橋本恵理, 河西千秋, 齋藤利和
  • Journal Title: アルコールと医生物 Volume: 33 Pages: 39-44
• [Presentation] 胎生期・青年期の二重ストレスで誘発されたうつ病モデルの病態解析. (2016)
  • Author(s): 古瀬研吾, 辻野華子, 木川昌康, 田山真矢, 鵜飼渉, 石井貴男, 橋本恵理, 河西千秋
  • Organizer: 第35回躁うつ病の薬理・生化学的研究懇話会
  • Place of Presentation: ホテルかめ福（山口県山口市）
  • Year and Date: 2016-11-04
• [Presentation] Ｌysophosphatidic acidはラットC6グリオーマのエクローシスを誘導し生存率を低下させる． (2016)
  • Author(s): 後藤玲央, 山田美佐, 橋本恵理,鵜飼渉, 山田光彦
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
• [Presentation] Pathological analysis of refractory depression using fetal alcohol and adolescent corticosterone double stress model. (2016)
  • Author(s): Furuse K, Tsujino H, Kigawa Y, Tayama M, Ukai W, Ishii T, Iwamoto T, Shiraishi M, Kobayashi S, Hashimoto E, Kawanishi C
  • Organizer: 30th CINP World Congress
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] 胎生期・青年期の二重ストレスで誘発されたうつ病モデルの病態解析． (2016)
  • Author(s): 鵜飼渉, 古瀬研吾, 辻野華子, 木川昌康, 田山真矢, 石井貴男, 橋本恵理, 河西千秋
  • Organizer: 第46回日本神経精神薬理学会
  • Place of Presentation: ソウル, 韓国
  • Year and Date: 2016-07-02
• [Presentation] 難治性うつ病の病態解析－胎児期・青年期二重ストレスモデルを用いた検討. (2016)
  • Author(s): 古瀬研吾, 辻野華子, 木川昌康, 田山真矢, 鵜飼渉, 石井貴男, 橋本恵理, 河西千秋
  • Organizer: 第112回日本精神神経学会
  • Place of Presentation: 幕張メッセ（千葉県千葉市）
  • Year and Date: 2016-06-02
• [Presentation] 胎生期アルコール曝露を組み合わせた難治化モデルを用いた解析． (2015)
  • Author(s): 古瀬研吾, 木川昌康, 辻野華子, 鵜飼渉, 石井貴男, 橋本恵理, 齋藤利和, 河西千秋.
  • Organizer: 平成27年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: 神戸国際会議場 (兵庫県神戸市）
  • Year and Date: 2015-10-11
• [Presentation] 統合失調症のシナプス形成異常：iPS細胞を用いたフィロポディア運動の解析． (2015)
  • Author(s): 鵜飼渉, 辻野華子, 木川昌康, 古瀬研吾, 中川裕一朗, 橋本恵理, 吉川武男, 河西千秋.
  • Organizer: 第34 回躁うつ病の薬理・生化学的研究懇話会
  • Place of Presentation: 夢海游淡路島 （兵庫県洲本市）
  • Year and Date: 2015-09-04
• [Presentation] Influence of combination therapy of ramelteon and trazodone on the management of delirium. (2015)
  • Author(s): Ishii T, Kakutani Y, Kigawa Y, Furuse K, Ukai W, Hashimoto E, Kawanishi C.
  • Organizer: The International College of Neuropsychopharmacology Theatic Meeting on Stress, Inflammation and Depression.
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2015-06-04
  • Int'l Joint Research
• [Presentation] Amelioration of treatment-refractory depression with intravenous stem cells: potential actions of boosting the antidepressant effect. (2015)
  • Author(s): Ukai W, Fueuse K, Kigawa Y, Tsujino H, Ishii T, Tayama M, Iwamoto T, Shiraishi M, Kobayashi S, Hashimoto E, Kawanishi C.
  • Organizer: The International College of Neuropsychopharmacology Theatic Meeting on Stress, Inflammation and Depression.
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2015-06-04
  • Int'l Joint Research
• [Presentation] Stem cell therapy: a regenerative approach for refractory psychiatric diseases. (2015)
  • Author(s): Ukai W, Furuse K, Kigawa Y, Tsujino H, Ishii T, Tayama M, Iwamoto T, Shiraishi M, Inoue K, Kobayashi S, Hashimoto E, Kawanishi C.
  • Organizer: Korean Society for Biochemistry and Molecular Biology International Conference 2015
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2015-05-12
  • Int'l Joint Research
• [Presentation] 難治性うつ病における血中BDNF高値の意義～海馬と側坐核の神経機能変化の比較解析から～ (2014)
  • Author(s): 古瀬研吾, 木川昌康, 辻野華子, 石井貴男, 鵜飼渉, 田山真矢, 橋本恵理, 齋藤利和
  • Organizer: 第33回躁うつ病の薬理・生化学的研究懇話会
  • Place of Presentation: 大丸別荘（福岡県筑紫野市）
  • Year and Date: 2014-10-17 – 2014-10-18
• [Presentation] Combined application of drug and stem cells for treating alcohol-induced brain damage and depression. (2014)
  • Author(s): Ukai W, Kigawa T, Ishii T, Furuse H, Tsujino H, Hashimoto E, Saito T.
  • Organizer: 16th International Society of Addiction Medicine Annual Meeting.
  • Place of Presentation: パシフィコ横浜会議センター（横浜市）
  • Year and Date: 2014-10-02 – 2014-10-06
• [Presentation] うつ病とアルコールによる脳障害を生物学的相同性から考える (2014)
  • Author(s): 橋本恵理, 石井貴男, 木川昌康, 古瀬研吾, 鵜飼渉, 齋藤利和
  • Organizer: 第11回日本うつ病学会
  • Place of Presentation: 広島国際会議場（広島市）
  • Year and Date: 2014-07-18 – 2014-07-19
  • Invited
• [Presentation] Stem cell therapy as a candidate treatment approach for neural plasticity change in alcohol-induced brain damage and depression. (2014)
  • Author(s): Ukai W, Kigawa Y, Hashimoto E, Ishii T, Furuse K, Tsujino H, Saito T.
  • Organizer: 29th CINP World Congress
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26