Involvement of aquaporin in the formation of optic nerve edema and protective effects of blocking the AQP channels.

• Project/Area Number: 25462763
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Osaka Medical College
• Principal Investigator: Oku Hidehiro 大阪医科大学, 医学部, 准教授 (90177163)
• Co-Investigator(Kenkyū-buntansha): Fukuhara Masayuki 大阪医科大学, 医学部, 非常勤講師 (00238510) ; Kobayashi Takatoshi 大阪医科大学, 医学部, 講師 (10567093) ; Okuno Takashi 大阪医科大学, 医学部, 非常勤講師 (20411366) ; Ikeda Tsunehiko 大阪医科大学, 医学部, 教授 (70222891) ; Ishizaki Eisuke 大阪医科大学, 医学部, 非常勤講師 (70530434) ; Takai Shinji 大阪医科大学, 医学部, 教授 (80288703) ; Kida Teruyo 大阪医科大学, 医学部, 講師 (90610105)
• Co-Investigator(Renkei-kenkyūsha): Hara Hideaki 岐阜大学, 薬学部, 教授 (20381717)
• Research Collaborator: Morishita Seita 大阪医科大学, 医学部, 大学院生 ; Kakurai Keigo 大阪医科大学, 医学部, 大学院生 ; Horie Taeko 大阪医科大学, 研究補助員
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: aquaporin / グルタミン酸 / 一酸化窒素 / 視神経挫滅 / アストロサイト / aquaporin 4 / TGN-020 / グルタミン / aquaporin-4 / aquaporin-9 / 視神経 / ラット

Outline of Final Research Achievements

Crushing the optic nerve of rats caued 1.8 fold increae of aquaporin 4 (AQP4) expression in the optic nerve. Exposure of optic nerve astrocytes to nitric oxide increased AQP4 expression and enlarged their volume.
Blocking the AQP4 channel by TGN-020 (5.0 mg/kg) caused more decrease of f retinal ganglion cells (RGCs). The ratio of BAX/Bcl-2 also supported the idea that blocking the AQP4 channel was neurodestructive. The glutamate level in the optic nerve was significantly increased after crushing the optic nerve, but TGN-020 depressed the expression of glutamate metabolism-related proteins. Exposure of cultured optic nerve astrocytes to glutamate increased the expression of AQP4 that was also depressed by TGN-020. In addition, glutamate uptake was inhibited by TGN-020. These results indicate that an inhibition of AQP4 enhances neuronal damages after crushing the optic nerve. Inhibition of AQP4 impairs glutamate metabolism which may account for these neurodestructive events.

Research Products

• [Journal Article] Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve. (2016)
  • Author(s): Nishikawa Y, Oku H, Morishita S, Horie T, Kida T, Mimura M, Fukumoto M, Kojima S, Ikeda T.
  • Journal Title: Exp Eye Res. Volume: 146 Pages: 118-127
  • DOI: 10.1016/j.exer.2015.12.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nitric Oxide Increases the Expression of Aquaporin-4 Protein in Rat Optic Nerve Astrocytes through the Cyclic Guanosine Monophosphate/Protein Kinase G Pathway. (2015)
  • Author(s): Oku H, Morishita S, Horie T, Kida T, Mimura M, Fukumoto M, Kojima S, Ikeda T.
  • Journal Title: Ophthalmic Res. Volume: 54 Pages: 212-221
  • DOI: 10.1159/000440846
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Systemic Simvastatin Rescues Retinal Ganglion Cells from Optic Nerve Injury Possibly through Suppression of Astroglial NF-κB Activation (2014)
  • Author(s): Morishita S, Oku H, Horie T, Tonari M, Kida T, Okubo A, Sugiyama T, Takai S, Hara H, Ikeda T.
  • Journal Title: PLoS One Volume: ９
  • DOI: 10.1371/journal.pone.0084387
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Changes in Expression of Aquaporin-4 and Aquaporin-9 in Optic Nerve after Crushing in Rats (2014)
  • Author(s): Hiroyuki Suzuki, Hidehiro Oku, Taeko Horie, Seita Morishita, Masahiro Tonari, Kazuma Oku, Akiko Okubo, Teruyo Kida, Masashi Mimura, Masanori Fukumoto, Shota Kojima, Shinji Takai, Tsunehiko Ikeda
  • Journal Title: PLoS One Volume: 9 Pages: 1-17
  • DOI: 10.1371/journal.pone.0114694
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] I nvolvement of P2X (7) receptors in retinal ganglion cell death after optic nerve crush injury in rats (2013)
  • Author(s): Kakurai K
  • Journal Title: Neuro Letters Volume: 534 Pages: 237-241
  • DOI: 10.1016/j.neulet.2012.11.060
  • Peer Reviewed
• [Journal Article] P2X(7) receptor activation may be involved in neuronal loss in the retinal ganglion cell layer after acute elevation of intraocular pressure in rats. (2013)
  • Author(s): Sugiyama T, Lee SY, Horie T, Oku H, Takai S, Tanioka H, Kuriki Y, Kojima S, Ikeda T.
  • Journal Title: Mol Vis. Volume: １９ Pages: 2080-2091
  • Peer Reviewed
• [Presentation] 視神経挫滅モデルにおけるaquaporin 4阻害剤の神経保護作用の検討 (2015)
  • Author(s): 奥 英弘、森下清太、堀江妙子、三村真士、福本雅格、喜田照代、池田恒彦
  • Organizer: 第119回日本眼科学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-04-16 – 2015-04-19
• [Presentation] 視神経挫滅モデルにおけるaquaporin 4阻害剤による神経保護作用の検討 (2015)
  • Author(s): 奥 英弘, 森下 清太, 堀江 妙子, 三村 真士, 福本 雅格, 喜田 照代, 池田 恒彦
  • Organizer: 第119回日本眼科学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-04-16
• [Presentation] 低酸素負荷による視神経アストロサイトでのAQP4およびAQP9の発現変化と一酸化窒素の関与 (2014)
  • Author(s): 奥 英弘、森下清太、堀江妙子、大久保安希子、喜田照代、池田恒彦
  • Organizer: 第118回日本眼科学会総会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] ラット視神経傷害時のaquaporin 4(AQP4)およびAQP9の発現変化 (2013)
  • Author(s): 奥 英弘,森下 清太, 戸成 匡宏, 堀江 妙子, 喜田 照代, 池田 恒彦
  • Organizer: 第117回日本眼科学会総会
  • Place of Presentation: 東京国際フォーラム
• [Remarks] 大阪医科大学眼科学教室
  • URL: http://www.osaka-med.ac.jp/deps/opt/kyousitu.html
• [Remarks] 大阪医科大学眼科学教室
  • URL: http://www.osaka-med.ac.jp/deps/opt/