Neuroprotective effect of PACAP against retinal damage in Glaucoma via immunomoduration

• Project/Area Number: 24592681
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Showa University
• Principal Investigator: Seki Tamotsu 昭和大学, 医学部, 客員教授 (10245855)
• Co-Investigator(Kenkyū-buntansha): NAKAMACHI Tomoya 富山大学, 大学院理工学研究部(理学), 助教 (30433840) ; WATANABE Jun 昭和大学, 遺伝子組換え実験室, 助教 (50649069)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); 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); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PACAP / 緑内障 / 神経保護作用 / 神経保護 / マイクログリア / マクロファージ / 神経節細胞 / NMDA / 免疫

Outline of Final Research Achievements

In this study, we examined the effect of ｐituitary adenylate cyclase-activating polypeptide (PACAP) on retinal ganglion cell (RGC) death in Glaucoma model mice.
When PACAP was co-administered with NMDA, significantly increased RGC survival at day 7, and a decrease in the number of TUNEL-positive RGCs at day 3 were observed.
The injection of PACAP significantly increased the number of retinal microglia/macrophage (MG/MΦ). PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.

Research Products

• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. (2016)
  • Author(s): Matsumoto M, Nakamachi T, Watanabe J, Sugiyama K, Ohtaki H, Murai N, Sasaki S, Xu Z, Hashimoto H, Seki T, Miyazaki A, Shioda S.
  • Journal Title: J Mol Neurosci Volume: 10 Issue: 2 Pages: 1007-1007
  • DOI: 10.1007/s12031-016-0731-x
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PACAP as a neuroprotective factor in ischemic neuronal injuries. (2015)
  • Author(s): Shioda S, Nakamachi T
  • Journal Title: Peptides Volume: 72 Pages: 202-207
  • DOI: 10.1016/j.peptides.2015.08.006
  • Peer Reviewed
• [Journal Article] PACAP Attenuates NMDA-Induced Retinal Damage in Association with Modulation of the Microglia/Macrophage Status into an Acquired Deactivation Subtype. (2013)
  • Author(s): Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Tsuchida M, Yoshikawa A, Matkovits A, Kagami N, Imai N, Fujisaka S, Usui I, Tobe K, Koide R, Takahashi H, Shioda S
  • Journal Title: J Mol Neurosci. Volume: 51(2) Issue: 2 Pages: 493-502
  • DOI: 10.1007/s12031-013-0017-5
  • Peer Reviewed
• [Journal Article] 糖尿病網膜症について (2013)
  • Author(s): 関 保
  • Journal Title: 蒲田医師会雑誌 Volume: 91 Pages: 36-36
• [Journal Article] 精密かつ体に優しい画像診断装置OCT (2013)
  • Author(s): 関 保
  • Journal Title: 蒲田医師会学術誌 Volume: in press
• [Journal Article] 東京都大田区における緑内障検診について (2013)
  • Author(s): 関 保、真木剛浩、下村直樹、濱畑和男
  • Journal Title: 大田区医学会誌 Volume: in press
• [Journal Article] Distribution and protective function of pituitary adenylate cyclase-activating polypeptide in the retina. (2012)
  • Author(s): Nakamachi Tomoya
  • Journal Title: Front Endocrinol (Lausanne) Volume: 3 Pages: 145-145
  • DOI: 10.3389/fendo.2012.00145
  • Peer Reviewed
• [Journal Article] 大田区における緑内障検診 (2012)
  • Author(s): 関 保、濱畑和男、下村直樹、籾木伊津穂、儘田直久
  • Journal Title: 大田区医学会誌 Volume: 4 Pages: 58-61
• [Presentation] エクリン汗腺におけるPACAPの汗分泌促進作用 (2016)
  • Author(s): 渡邊潤, 佐々木駿, 中町智哉, 大滝博和, 荒田悟, 本田一穂, 塩田清二
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-05-13
• [Presentation] マウスにおけるPACAPの唾液分泌促進作用 (2016)
  • Author(s): 中町智哉, 渡邊 潤, 塩田清二
  • Organizer: 第121回日本解剖学会総会全国学術集会
  • Place of Presentation: 郡山
  • Year and Date: 2016-03-28
• [Presentation] Pituitary adenylate cyclase-activating polypeptide promotes eccrine sweat secretion. (2015)
  • Author(s): Shun Sasaki, Jun Watanabe, Hirokazu Ohtaki, Akira Miyazaki, Seiji Shioda, Hirohiko Sueki
  • Organizer: 日本研究皮膚科学会 第40回年次学術大会・総会.
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
• [Presentation] Effects of PACAP on the secretions of tear and saliva in mouse. (2015)
  • Author(s): Nakamachi T, Watanabe J, Seki T, Ohtaki H, Shioda S.
  • Organizer: Neuropeptides 2015.
  • Place of Presentation: Aberdeen, UK
  • Year and Date: 2015-09-28
  • Int'l Joint Research / Invited
• [Presentation] Involvment of PACAP in differentiation of neural progenitor cells via radial glia. (2015)
  • Author(s): Watanabe J, Ohtaki H, Nakamachi T, Sasaki S, Matsumoto M, Murai N, Seki T, Arata S, Shioda S.
  • Organizer: 12th International Symposium in VIP, PACAP and Related Peptides.
  • Place of Presentation: Cappadokia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] PACAP attenuates retinal damage in association with modulation of the microglia/macrophage status and cytokines expression (2015)
  • Author(s): Nakamachi T, Wada Y, Endo K, Seki T, Shioda S.
  • Organizer: 12th International Symposium in VIP, PACAP and Related Peptides.
  • Place of Presentation: Cappadokia, Turkey
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] PACAPの唾液および汗分泌促進作用 (2015)
  • Author(s): 中町智哉, 渡邊 潤, 佐々木駿, 塩田清二
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-15
• [Presentation] Role of PACAP for impairment of cornea epithelial wound healing (2014)
  • Author(s): Tamotsu Seki, Tomoya Nakamachi, Jozsef Farkas, Jun Watanab, Sachiko Izumi, Seiji Shioda
  • Organizer: Anual European Association for Vision and Eye Research Congress
  • Place of Presentation: Nice, France
  • Year and Date: 2014-10-01 – 2014-10-04
• [Presentation] Expression and localization of IL-6 and PACAP receptor in mouse brain after global ischemia (2013)
  • Author(s): Nakamachi T, Kagami N, Hori M, Yoshikawa A, Sugiyama K, Imai N, Seki T, Arata S, Shioda S
  • Organizer: Society for Neuroscience's 43rd annual meeting
  • Place of Presentation: San Diego, CA, USA
• [Presentation] 緑内障モデルマウスを用いたPACAPの網膜保護機構の検討～マイクログリア/マクロファージの関与～ (2013)
  • Author(s): 中町 智哉、和田 悦洋、 関 保、 加賀美 信幸、 今井 ノリ、 荒田 悟、 塩田 清二
  • Organizer: 第60回日本実験動物学会総会
  • Place of Presentation: つくば市、茨木
• [Presentation] マウスにおけるPACAPの角膜傷害治癒効果の検討 (2013)
  • Author(s): 中町 智哉、Forkas Jozsef, 和田 悦洋、関 保、Matkovits Attila、加賀美 信幸、土田 将史、吉川 輝、杉山 公一、今井 ノリ、荒田 悟、塩田 清二
  • Organizer: 第118回日本解剖学会総会・全国学術集会
  • Place of Presentation: 香川, サンポートホール高松
• [Presentation] 神経ペプチドPACAPの網膜保護効果における網膜局所免疫環境の変化についての検討－網膜保護効果へのマイクログリア／マクロファージとTGF-βの寄与－ (2012)
  • Author(s): 中町智哉・和田悦洋・遠藤貴美・中村圭輔・堀元英・土川大介・吉川輝・土田将史・加賀美信幸・今井ノリ・関保・小出良平・塩田清二
  • Organizer: 第9回GPCR研究会
  • Place of Presentation: 東京,科学未来館
• [Presentation] PACAP stimulates tear secretion in mouse (2012)
  • Author(s): T. Nakamachi, Y. Aizawa, H. Ohtaki, S. Yofu, Y. Wada, T. Seki, S. Arata, N. Shintani, H. Hashimoto, A. Baba and Seiji Shioda
  • Organizer: 19th International Symposium on Regulatory Peptides
  • Place of Presentation: Copenhagen, Denmark
• [Presentation] PACAP suppresses retinal neuronal damage through modulation of the activation state of retinal microglia/macrophage (2012)
  • Author(s): Nakamachi T, Wada Y, Seki T, Tsuchikawa D, Hori M, Tsuchida M, Yoshikawa A, Matkovits A, Kagami N, Imai N, Arata S and Shioda S
  • Organizer: The 42th Annual Meeting of the Society for Neuroscience
  • Place of Presentation: New Orleasns, LA
• [Book] PACAP and neural development. In: Pituitary Adenylate Cyclase Activating Polypeptide – PACAP, (Eds. Reglodi D and Tamas A) (2016)
  • Author(s): Watanabe J, Seki T, Shioda S
  • Publisher: New York: Springer Nature (New York)
• [Book] Chapter 18A. “Secretin” In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Nakamachi T
  • Total Pages: 2
  • Publisher: Elsevier (USA)
• [Book] Chapter 18C. “Pituitary Adenylate Cyclase-Activating Polypeptide“ In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Nakamachi T
  • Total Pages: 2
  • Publisher: Elsevier (USA)
• [Book] Chapter 18D. “Pituitary Adenylate Cyclase-Activating Polypeptide-Related Peptide“ In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Nakamachi T
  • Total Pages: 2
  • Publisher: Elsevier (USA)
• [Book] Chapter 18E. "Vasoactive intestinal peptide". In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Watanabe J
  • Total Pages: 3
  • Publisher: Elsevier (USA)
• [Book] Chapter 18F. Peptide histidine isoleucine/methionine. In: Handbook of Hormones: Comparative and General Endocrinology (Eds. Takei Y, Ando H, Tsutsui K) (2015)
  • Author(s): Watanabe J
  • Total Pages: 2
  • Publisher: Elsevier (USA)
• [Remarks] 昭和大学医学部解剖学講座顕微解剖学部門
  • URL: http://www.showa-u.ac.jp/sch/med/major/anat-1/index.html
• [Remarks] たまがわ眼科クリニック研究業績集
  • URL: http://home.c02.itscom.net/tamagawa/newpage10.html