Determination of stress sensitivity molecules that exacerbate depression after head injury

• Project/Area Number: 24592133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Kochi University
• Principal Investigator: HIGASHI Youichirou 高知大学, 教育研究部医療学系, 助教 (80380062)
• Co-Investigator(Kenkyū-buntansha): YAWATA Toshio 高知大学, 教育研究部医療学系, 助教 (40380323) ; UEBA Tetsuya 高知大学, 教育研究部医療学系, 教授 (00314203) ; FUJIMOTO Yasunori 高知大学, 教育研究部医療学系, 講師 (80589789) ; SHIMIZU Keiji 高知大学, 教育研究部医療学系, 教授 (70116044)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 頭部外傷 / うつ病 / 脳内亜鉛 / グリア細胞 / 脳保護薬 / 活性酸素 / 5-lipoxygenase / アストロサイト

Outline of Final Research Achievements

We examined whether complex polysaccharide and lipopolysaccharide effect on concussion-induced depressive-like behavior in mice, but they had no effect on depressive-like behavior in the forced swim test.
Furthermore, we investigated the effect of a membrane-permeable zinc chelater (ZC) or a free radical scavenger edaravone (Ed) on concussion-induced depressive-like behavior. Mice were intravenously administered ZC and Ed before and immediately after impact, respectively. We found that ZC suppressed depressive-like behavior and microglial activation in the hippocampus 1 day after concussion. Ed also attenuated concussion-induced depressive-like behavior, which was accompanied by inhibition of increased hippocampal oxidative stress and suppression of 5-lipoxygenase activation in hippocampal astrocytes. These results suggest that ZC and Ed protect against concussion-induced depression, and these protections are mediated by suppression of glial cell-associated brain inflammation.

Research Products

• [Journal Article] Elevated Cell Invasion in a Tumor Sphere Culture of RSV-M Mouse Glioma Cells (2015)
  • Author(s): Nonaka M, Yawata T, Takemura M, Higashi Y, Nakai E, Shimizu K, Ueba T.
  • Journal Title: Neurologia medico-chirurgica Volume: 55 Issue: 1 Pages: 60-70
  • DOI: 10.2176/nmc.oa.2014-0067
  • NAID: 130004922269
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat. (2015)
  • Author(s): Shimizu T, Tanaka K, Shimizu S, Higashi Y, Yawata T, Nakamura K, Taniuchi K, Ueba T, Yuri K, Saito M.
  • Journal Title: Neuropharmacology. Volume: 95 Pages: 278-289
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin II acting on brain AT1 receptors induces adrenaline secretion and pressor responses in the rat. (2014)
  • Author(s): Nakamura K, Shimizu T, Yanagita T, Nemoto T, Taniuchi K, Shimizu S, Dimitriadis F, Yawata T, Higashi Y, Ueba T, Saito, M
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 7248-7248
  • DOI: 10.1038/srep07248
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of oxidative stress and 5-lipoxygenase activation by edaravone improves depressive-like behavior after concussion (2014)
  • Author(s): Higashi Y., Hoshijima M., Yawata T., Nobumoto A., Tsuda M., Shimizu T., Saito M., Ueba T.
  • Journal Title: J Neurotrauma Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat (2014)
  • Author(s): Shimizu T, Tanaka K, Nakamura K, Taniuchi K, Yawata T, Higashi Y, Ueba T, Dimitriadis F, Shimizu S, Yokotani K, Saito M.
  • Journal Title: Neuropharmacology Volume: 82 Pages: 19-27
  • DOI: 10.1016/j.neuropharm.2014.03.005
  • Peer Reviewed / Open Access
• [Journal Article] Central bombesin possibly induces S-nitrosylation of cyclooxygenase-1 in pre-sympathetic neurons of rat hypothalamic paraventricular nucleus (2014)
  • Author(s): Tanaka K, Shimizu T, Higashi Y, Nakamura K, Taniuchi K, Dimitriadis F, Shimizu S, Yokotani K, Saito M.
  • Journal Title: Life Sci. Volume: 100 Issue: 2 Pages: 85-96
  • DOI: 10.1016/j.lfs.2014.01.079
  • Peer Reviewed
• [Journal Article] Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models. (2013)
  • Author(s): Asanuma, M., Miyazaki, I., Diaz-Corrales, F.J., Higashi, Y., Namba, M. and Ogawa, N.
  • Journal Title: PLoS ONE Volume: 8 Issue: 6 Pages: e65983-e65983
  • DOI: 10.1371/journal.pone.0065983
  • NAID: 120005702491
  • Peer Reviewed
• [Journal Article] NAD+ influx through connexin hemichannels prevents poly(ADP-ribose) polymerase-mediated astrocyte death. (2013)
  • Author(s): Okuda H, Nishida K, Higashi Y, Nagasawa K.
  • Journal Title: Life Science Volume: 92 Issue: 13 Pages: 808-814
  • DOI: 10.1016/j.lfs.2013.02.010
  • Peer Reviewed
• [Journal Article] Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury. (2013)
  • Author(s): Ohta M
  • Journal Title: Brain Research Volume: 1490 Pages: 184-192
  • DOI: 10.1016/j.brainres.2012.09.011
  • Peer Reviewed
• [Presentation] 亜鉛誘導活性化ミクログリアの機能解析 (2014)
  • Author(s): 東 洋一郎、八幡 俊男、政平 貴訓、中居 永一、野中 大伸、竹 村 光広、上羽 哲也
  • Organizer: 第４回 メタロミクス研究フォーラム
  • Place of Presentation: 武蔵野大学 (東京都西東京市)
  • Year and Date: 2014-11-07 – 2014-11-08
• [Presentation] Suppression of 5-lipoxygenase activation by edaravone improves depressive-like behavior after concussion (2014)
  • Author(s): 東 洋一郎、星島 陸宏、八幡 俊男、政平 貴訓、中居 永一、川西 裕、野中 大伸、竹村 光広、上羽 哲也
  • Organizer: 第57回日本神経化学会
  • Place of Presentation: 奈良県文化会館 (奈良県奈良市)
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] 頭部外傷後のうつ病様行動に対するエダラボンの効果の解析 (2014)
  • Author(s): 東 洋一郎、星島 陸宏、八幡 俊男、政平 訓貴、中居 永一、川西 裕、野中 大伸、竹村 光広、上羽 哲也
  • Organizer: 第134回日本薬学会年会
  • Place of Presentation: 熊本
• [Presentation] 頭部外傷後のうつ病様行動に対するエダラボンの効果の解析 (2013)
  • Author(s): 東 洋一郎、星島 陸宏、八幡 俊男、政平 訓貴、中居 永一、川西 裕、野中 大伸、竹村 光広、上羽 哲也
  • Organizer: 第14回日本分子脳神経外科学会
  • Place of Presentation: 横浜
• [Presentation] 頭部外傷後うつ病発症に対する脳内亜鉛の関与 (2013)
  • Author(s): 東 洋一郎、星島 陸宏、八幡 俊男、政平 訓貴、中居 永一、川西 裕、野中 大伸、竹村 光広、上羽 哲也
  • Organizer: 第9回メタルバイオサイエンス研究会
  • Place of Presentation: 静岡
• [Presentation] エダラボンは頭部外傷による軸索損傷を阻止し、記憶障害を改善する (2013)
  • Author(s): 東 洋一郎、大田 学、北原 正大、野中 大伸、八幡 俊男、上羽 哲也
  • Organizer: 第36回日本神経科学会
  • Place of Presentation: 京都
• [Presentation] Edaravone supresses axonal injury and improves memory dysfunction after traumatic brain injury in mice (2012)
  • Author(s): Higashi Y, Ohta M, YawataT, Kitahara M, Fujimoto Y, Shimizu K
  • Organizer: 35回日本神経科学大会
  • Place of Presentation: 名古屋（名古屋国際会議場）
• [Presentation] 頭部外傷による軸索損傷と認知機能障害に対するエダラボンの効果の解析 (2012)
  • Author(s): 大田 学、東 洋一郎、北原 正大、八幡 俊男、星島 陸宏、藤本康 倫、清水 恵司
  • Organizer: 第１３回日本分子脳神経外科学会
  • Place of Presentation: 熊本（熊本市国際交流会館）