Effect of PACAP for prevention/treatment of dry eye syndrome

• Project/Area Number: 24592680
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: University of Toyama (2013-2014); Showa University (2012)
• Principal Investigator: NAKAMACHI Tomoya 富山大学, 大学院理工学研究部(理学), 助教 (30433840)
• Co-Investigator(Renkei-kenkyūsha): SEKI Tamotsu 昭和大学, 医学部, 兼任講師 (10245855) ; SHIODA Seiji 昭和大学, 医学部, 教授 (80102375)
• 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ドライアイ / PACAP / 涙液分泌 / 角膜傷害 / マウス / 点眼 / 角膜上皮 / 涙液 / 角膜

Outline of Final Research Achievements

The dry eye syndrome is one of the most common eye ailments caused by volume reduction or the altered quality of tears with corneal damage, however, an effective treatment has yet to be established. Here we demonstrated that PACAP eye drop stimulates tear secretion via PAC1R in mouse. Moreover, AQP5 siRNA treatment to lacrimal gland attenuates PACAP-induced tear secretion. These results suggest a possible role of PACAP as a regulator of tear secretion through AQP5. On the other hand, PACAP have direct pathway to affect the mouse cornea. PAC1R mRNA and its immunoreactivity were detected in mouse corneal epithelium. In corneal injury model mice, PACAP eye drop significantly reduced the injured area, and the effect was disappeared by co-treatment with PACAP receptor antagonists. These data suggest that PACAP has dual function, stimulator for tear secretion and protectant for corneal damage. PACAP could be a good candidate for an eye-drop medicine for the dry eye syndrome.

Research Products

• [Journal Article] Comparison of expression and proliferative effect of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors on human astrocytoma cell lines. (2014)
  • Author(s): Nakamachi T, Sugiyama K, Watanabe J, Imai N, Kagami N, Hori M, Arata S, Shioda S.
  • Journal Title: J Mol Neurosci. Volume: 54(3) Issue: 3 Pages: 388-394
  • DOI: 10.1007/s12031-014-0362-z
  • Peer Reviewed
• [Journal Article] PACAP stimulates functional recovery after spinal cord injury through axonal regeneration. (2014)
  • Author(s): Tsuchida M, Nakamachi T, Sugiyama K, Tsuchikawa D, Watanabe J, Hori M, Yoshikawa A, Imai N, Kagami N, Matkovits A, Atsumi T, Shioda S.
  • Journal Title: J Mol Neurosci. Volume: 54(3) Issue: 3 Pages: 380-387
  • DOI: 10.1007/s12031-014-0338-z
  • Peer Reviewed
• [Journal Article] PACAP38 differentially effects genes and CRMP2 protein expression in ischemic core and penumbra regions of permanent middle cerebral artery occlusion model mice brain. (2014)
  • Author(s): Hori M, Nakamachi T, Shibato J, Rakwal R, Tsuchida M, Shioda S, Numazawa S.
  • Journal Title: Int J Mol Sci. Volume: 15(9) Issue: 9 Pages: 17014-17034
  • DOI: 10.3390/ijms150917014
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors. (2014)
  • Author(s): Nakamura K, Nakamachi T, Endo K, Ito K, Machida T, Oka T, Hori M, Ishizaka K, Shioda S.
  • Journal Title: Andrologia. Volume: 46(5) Issue: 5 Pages: 465-71
  • DOI: 10.1111/and.12102
  • Peer Reviewed
• [Journal Article] Low dose of methylmercury (MeHg) exposure induces caspase mediated-apoptosis in cultured neural progenitor cells. (2013)
  • Author(s): Watanabe J, Nakamachi T, Ohtaki H, Naganuma A, Shioda S, Nakajo S
  • Journal Title: The Journal of Toxicological Sciences Volume: 38(6) Pages: 931-5
  • NAID: 130004447097
  • Peer Reviewed
• [Journal Article] Autocrine effects of neuromedin B stimulate the proliferation of rat primary osteoblasts. (2013)
  • Author(s): Saito H, Nakamachi T, Inoue K, Ikeda R, Kitamura K, Minamino N, Shioda S, Miyata A.
  • Journal Title: Journal of Endocrinology Volume: 15;217(2) Issue: 2 Pages: 141-50
  • DOI: 10.1530/joe-12-0488
  • 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] Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor expression in reactive astrocytes induced by global brain ischemia in mice. (2013)
  • Author(s): Nakamachi T, Jozsef F, Kagami N, Wada Y, Hori M, Tsuchikawa D, Tsuchida M, Yoshikawa A, imai N, Hata A, Atrata S, Shioda S
  • Journal Title: Acta Neurochir Suppl Volume: 118 Pages: 55-59
  • DOI: 10.1007/978-3-7091-1434-6_9
  • ISBN: 9783709114339, 9783709114346
  • Peer Reviewed
• [Journal Article] Impaired response to hypoxia in the respiratory center is a major cause of neonatal death of the PACAP-knockout mouse. (2013)
  • Author(s): Arata S, Nakamachi T, Onimaru H, Hashimoto H, Shioda S
  • Journal Title: Eur J Neurosci. Volume: 37(3) Pages: 407-16
  • Peer Reviewed
• [Journal Article] IL-6 and PACAP receptor expression and localization after global brain ischemia in mice. (2012)
  • Author(s): Nakamachi T, Tsuchida M, Kagami N, Yofu S, Wada Y, Hori M, Tsuchikawa D, Yoshikawa A, Imai N, Nakamura K, Arata S, Shioda S.
  • Journal Title: J Mol Neurosci Volume: 48(3) Issue: 3 Pages: 518-525
  • DOI: 10.1007/s12031-012-9819-0
• [Journal Article] Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury. (2012)
  • Author(s): Tsuchikawa D, Nakamachi T, Tsuchida M, Wada Y, Hori M, Farkas J, Yoshikawa A, Kagami N, Imai N, Shintani N, Hashimoto H, Atsumi T, Shioda S.
  • Journal Title: J Mol Neurosci. Volume: 48(3) Issue: 3 Pages: 508-17
  • DOI: 10.1007/s12031-012-9817-2
  • Peer Reviewed
• [Journal Article] Intranasal administration of PACAP: uptake by brain and regional brain targeting with cyclodextrins. (2012)
  • Author(s): Nonaka N, Farr SA, Nakamachi T, Morley JE, Nakamura M, Shioda S, Banks WA.
  • Journal Title: Peptides Volume: 36(2) Pages: 168-75
  • Peer Reviewed
• [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] Transcriptomics and proteomics analyses of the PACAP38 influenced ischemic brain in permanent middle cerebral artery occlusion model mice (2012)
  • Author(s): Hori M, Nakamachi T, Rakwal R, Shibato J, Ogawa T, Aiuchi T, Tsuruyama T, Tamaki K, Shioda S
  • Journal Title: J Neuroinflammation Volume: 9 Issue: 1 Pages: 256-256
  • DOI: 10.1186/1742-2094-9-256
  • Peer Reviewed
• [Journal Article] 中町 智哉、塩田 清二 (2012)
  • Author(s): 神経保護因子としてのPACAP
  • Journal Title: 生化学誌 Volume: 84(7) Pages: 566-9
  • Peer Reviewed
• [Presentation] Role of PACAP in Memory and Learning. (2015)
  • Author(s): Tomoya Nakamachi
  • Organizer: The 2nd Tenure Track System International Symposium
  • Place of Presentation: 富山
  • Year and Date: 2015-03-04
• [Presentation] マウスの涙液分泌調節機構におけるPACAPの役割 (2014)
  • Author(s): 中町 智哉，大滝 博和，渡邊 潤，関 保，塩田 清二
  • Organizer: 日本動物学会 第85回仙台大会
  • Place of Presentation: 仙台
  • Year and Date: 2014-09-13
• [Presentation] PACAP stimulates tear secretion through AQP5 signal in mouse. (2014)
  • Author(s): Tomoya Nakamachi, Hirokazu Ohtaki, Jun Watanabe, Tamotsu Seki, Seiji Shioda
  • Organizer: 20th International Symposium on Regulatory Peptides (Regpep2014)
  • Place of Presentation: 京都
  • Year and Date: 2014-09-09
• [Presentation] PACAPの抗酸化誘導作用と加齢に伴う神経変性との関連 (2014)
  • Author(s): 中町 智哉, 大滝 博和, 渡邊 潤, 松田 恒平, 塩田 清二
  • Organizer: 第11回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-10
• [Presentation] PACAP stimulates the corneal healing via lacrimal-mediating and direct pathways in mouse (2013)
  • Author(s): Nakamachi, T
  • Organizer: 11th International Symposium on VIP, PACAP and Related Peptides
  • Place of Presentation: Pecs, Hungary
• [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: Neuroscience 2013, Society for Neuroscience's 43rd annual meeting.
  • Place of Presentation: San Diego, CA
• [Presentation] マウス硝子体内へのPACAP投与による網膜保護効果と局所免疫環境変化についての検討 (2013)
  • Author(s): 中町智哉, 和田悦洋, 関 保, 堀 元英, 吉川輝, 土田将史, 杉山公一, 加賀美信幸, 今井ノリ, 荒田悟, 塩田清二
  • Organizer: 第38回日本比較内分泌学会大会・第40回日本神経内分泌学会学術集会合同大会
  • Place of Presentation: 宮崎
• [Presentation] 緑内障モデルマウスを用いたPACAPのロ網膜保護機構の検討～マイクグリア/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: 筑波
• [Presentation] PACAPの抗酸化誘導作用と加齢性神経変性との関連 (2013)
  • Author(s): 中町智哉, 大滝博和, 渡邊潤, 吉川輝, 土田将史, 杉山公一, 加賀美信幸, 今井ノリ, 塩田清二
  • Organizer: 第119回日本解剖学会総会・全国学術集会
  • Place of Presentation: 自治医科大学（栃木）
• [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] 脳虚血後のマウス海馬におけるIL-6とPACAP受容体の発現動態 (2013)
  • Author(s): 中町 智哉、土田 将史、中村 圭輔、加賀美 信幸、吉川 輝、Matkovits Attila、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] Handbook of Biologically Active Peptides, 2nd Edition (2013)
  • Author(s): Abba Kastin
  • Total Pages: 2032
  • Publisher: Academic Press
• [Remarks] 富山大学大学院理工学研究部 テニュアトラック若手育成部門 テニュアトラック教員紹介
  • URL: http://www3.u-toyama.ac.jp/ritenure/scholar/nakamachi.html
• [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/
• [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