神経損傷防御の基盤研究とトランスレーショナルリサーチ

2015 Fiscal Year Annual Research Report

• Project/Area Number: 23249079
• Research Institution: Showa University
• Principal Investigator: 塩田 清二 星薬科大学, 付置研究所, 教授 (80102375)
• Co-Investigator(Kenkyū-buntansha): 土肥 謙二 東京慈恵会医科大学, 医学部, 講師 (20301509) ; 中町 智哉 富山大学, その他の研究科, 助教 (30433840) ; 宮田 篤郎 鹿児島大学, 医学部, 教授 (60183969) ; RAKWAL RANDEEP 筑波大学, 体育系, 教授 (70590850)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: PACAP / 神経細胞死防御 / ヒト骨髄間葉系幹細胞 / 神経損傷の防御 / ﾄﾗﾝｽﾚｰｼｮﾅﾙﾘｻｰﾁ

Outline of Annual Research Achievements

PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide)は、神経細胞の保護および神経修復・再生作用を有する神経ペプチドであり、神経損傷疾患の治療戦略に重要な役割を果たす。
我々はマウスの中大脳動脈閉塞による脳虚血後にPACAPを脳室内投与することでcollapsin response mediator protein 2（CRMP2）タンパク質の発現が投与6時間後で上昇し、CRMP2陽性反応が梗塞周囲のペナンブラ領域の神経細胞に強く認められることを発表した。同分子は軸索形成に重要な因子であることから、運動機能や軸索新生を評価するためにマウスの脊髄損傷モデルを用いた機能解析を行った。PACAP10-12 Ｍ添加群では生理的食塩水添加群と比較して損傷後14日目において有意な運動機能の回復が認められた。損傷後の脊髄ではCRMP2 mRNA発現量は投与後7日目で増加傾向を示し、14日目で有意差がみられた。CRMP2免疫陽性反応は脊髄の神経細胞に多くみられ、傷害後では傷害部と正常部の境界領域において強い陽性反応が観察された。大脳皮質への順行性トレーサー投与実験によりPACAP添加群では損傷領域近傍に新生・再生軸索が多数観察された。PACAPはCRMP2を介して損傷後の軸索再生を誘導することで運動機能の回復を促進する可能性が考えられた。
また人臨床への応用を行うためのトランスレーショナル研究として、マーモセットを用いた中大脳動脈閉塞モデルに対しPACAPを静脈内持続投与する実験を行っており、PACAPが血圧低下作用を示すこと、血糖値に作用する等の現象を確認している。脳梗塞や運動機能の解析については現段階ではまだ有意差は得られておらず個体数の増加または実験条件の再検討が必要であると考え、虚血モデルを含めて現在さらに研究を行っている。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Narcolepsy-like sleep disturbance in orexin knockout mice are normalized by the 5-HT1A receptor agonist 8-OH-DPAT. (2016)
  • Author(s): Mori T, Uzawa N, Iwase Y, Masukawa D, Rahmadi M, Hirayama S, Hokazono M, Higashiyama K, Shioda S, Suzuki T
  • Journal Title: Psychopharmacology(Berl) Volume: Epub ahead of print Pages: 1-11
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP-specific receptor. (2016)
  • Author(s): Xu Z, Ohtaki H, Watanabe J, Miyamoto K, Murai N, Sasaki S, Matsumoto M, Hashimoto H, Hiraizumi Y, Numazawa S, Shioda S
  • Journal Title: Sci Rep Volume: 6 Pages: 22373
  • DOI: 10.1038/srep22373
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: 6 Pages: 1-10
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Opioid systems in the lateral hypothalamus regulate feeding behavior through orexin and GABA neurons. (2016)
  • Author(s): Ardianto C, Yonemochi N, Yamamoto S, Yang L, Takenoya F, Shioda S, Nagase H, Ikeda H, Kamei J
  • Journal Title: Neuroscience Volume: 320 Pages: 183-193
  • DOI: 10.1016/j.neuroscience.2016.02.002. Epub 2016 Feb 6
  • Peer Reviewed
• [Journal Article] A new Xist allele driven by a constitutively active promoter is dominated by Xist locus environment and exhibits the parent-of-origin effects. (2015)
  • Author(s): Amakawa Y, Sakata Y, Hoki Y, Arata S, Shioda S, Fukagawa T, Sasaki H, Sado T
  • Journal Title: Development Volume: 142 Pages: 4299-4308
  • DOI: 10.1242/dev.128819. Epub 2015 Oct 28
  • Peer Reviewed
• [Journal Article] Two-color Dye-swap DNA Microarray approach toward confident gene expression profiling in PMCAO mouse model for ischemia-related and PACAP38-influenced genes. (2015)
  • Author(s): Hori M, Shibato J, Nakamachi T, Rakwal R, Ogawa T, Shioda S, Numazawa S
  • Journal Title: Genom Data Volume: 22 Pages: 148-154
  • DOI: 10.1016/j.gdata.2015.01.007. eCollection 2015
  • Peer Reviewed / Open Access
• [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. Epub 2015 Aug 11
  • Peer Reviewed
• [Journal Article] Unraveling the Rat Intestine, Spleen and Liver Genome-Wide Transcriptome after the Oral Administration of Lavender Oil by a Two-Color Dye-Swap DNA Microarray Approach. (2015)
  • Author(s): Kubo H, Shibato J, Saito T, Ogawa T, Rakwal R, Shioda S
  • Journal Title: PLoS One Volume: 10 Pages: e0129951
  • DOI: 10.1371/journal.pone.0129951. eCollection 2015
  • Peer Reviewed / Open Access
• [Journal Article] Distinct effects of the serotonin-noradrenaline reuptake inhibitors milnacipran and venlafaxine on rat pineal monoamines. (2015)
  • Author(s): Muneoka K, Kuwagata M, Ogawa T, Shioda S
  • Journal Title: Neuroreport. Volume: 26 Pages: 510-514
  • DOI: 10.1097/WNR.0000000000000379
  • Peer Reviewed
• [Journal Article] Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40. (2015)
  • Author(s): Karki P, Kurihara T, Nakamachi T, Watanabe J, Asada T, Oyoshi T, Shioda S, Yoshimura M, Arita K, Miyata A
  • Journal Title: Mol Pain Volume: 11 Pages: 6
  • DOI: 10.1186/s12990-015-0003-8
  • Peer Reviewed / Open Access
• [Journal Article] Neuropeptide W-Induced Hypophagia is Mediated Through Corticotropin-Releasing Hormone-Containing Neurons. (2015)
  • Author(s): Takenoya F, Wang L, Kageyama H, Hirako S, Wada N, Hashimoto H, Ueta Y, Sakagami J, Nonaka N, Shioda S
  • Journal Title: J Mol Neurosci Volume: 56 Pages: 789-798
  • DOI: 10.1007/s12031-015-0501-1. Epub 2015 Feb 19
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comprehensive analysis of neonatal versus adult unilateral decortication in a mouse model using behavioral, neuroanatomical, and DNA microarray approaches. (2015)
  • Author(s): Yoshikawa A, Nakamachi T, Shibato J, Rakwal R, Shioda S
  • Journal Title: Int J Mol Sci Volume: 15 Pages: 22492-22517
  • DOI: 10.3390/ijms151222492
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Intranasal administration of GALP suppressed the lipid accumulation in the liver. (2016)
  • Author(s): Hirako S, Kageyama H, Takaenoya F, Wada N, Okabe M, Shioda S.
  • Organizer: 13th International Congress on Obesity
  • Place of Presentation: バンクーバー、カナダ
  • Year and Date: 2016-05-01 – 2016-05-04
• [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 – 2016-03-30
• [Presentation] Impairment of memory and learning and hippocampal oxidative damage in aged PACAP deficient mouse. (2015)
  • Author(s): Nakamachi, T., Matsuda, K., and Shioda, S.
  • Organizer: CompBiol 2015
  • Place of Presentation: 広島
  • Year and Date: 2015-12-11 – 2015-12-13
• [Presentation] Effects of PACAP on the secretions of tear and saliva in mouse. (2015)
  • Author(s): Nakamachi, T., Watanabe, J., Seki, T., Ohtaki, H., and Shioda, S.,
  • Organizer: Neuropeptide 2015
  • Place of Presentation: アバディーン、イギリス
  • Year and Date: 2015-09-28 – 2015-10-01
  • Int'l Joint Research
• [Presentation] Crucial role of PACAP in neural progenitor cells during development and after degeneration. (2015)
  • Author(s): Watanabe, J., Ohtaki, H., Nakamachi, T., Matsumoto, M., Sasaki, S., Murai, N., Arata, S., and Shioda, S.,
  • Organizer: Neuropeptide 2015
  • Place of Presentation: アバディーン、イギリス
  • Year and Date: 2015-09-28 – 2015-10-01
  • 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., and Shioda, S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: カッパドキア、トルコ
  • Year and Date: 2015-09-21 – 2015-09-26
  • Int'l Joint Research
• [Presentation] Neuroprotective effect of PACAP on spinal cord injury through CRMP2 protein. (2015)
  • Author(s): Shioda, S., Takenoya, F., Hori, M., Shibato, J., Nakamachi, T., and Rakwal, R
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: カッパドキア、トルコ
  • Year and Date: 2015-09-21 – 2015-09-26
  • Int'l Joint Research
• [Presentation] Involvement 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., and Shioda, S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides,
  • Place of Presentation: カッパドキア、トルコ
  • Year and Date: 2015-09-21 – 2015-09-26
  • Int'l Joint Research
• [Presentation] PACAP contributes proliferation of hippocampal neural stem/progenitor cells after global ischemia in mice. (2015)
  • Author(s): Nakamachi, T., Ohtaki, H., Watanabe, J., and Shioda, S.
  • Organizer: 12th international symposium on VIP/PACAP and related peptides
  • Place of Presentation: カッパドキア、トルコ
  • Year and Date: 2015-09-21 – 2015-09-26
  • Int'l Joint Research
• [Presentation] PACAP 遺伝子欠損マウスにおける加齢に伴う学習記憶障害 (2015)
  • Author(s): 中町智哉, 松田恒平, 塩田清二
  • Organizer: 日本動物学会第86回大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-17 – 2015-05-19
• [Presentation] GALPによる自律神経系を介した脂質代謝調節機構 (2015)
  • Author(s): 平子哲史、竹ノ谷文子、和田亘弘、塩田清二
  • Organizer: 第12回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-15 – 2015-05-16
• [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 – 2015-05-16
• [Presentation] Effect of intranasal GALP on obesity and hepatic lipid metabolism in obese mice. (2015)
  • Author(s): Hirako S, Kageyama H, Takaenoya F, Wada N, Okabe M, Shioda S
  • Organizer: 12th Asian Congress of Nutrition.
  • Place of Presentation: 横浜
  • Year and Date: 2015-05-14 – 2015-05-18
• [Book] 特集 未病・健康ー病気にならないための衣・食・住そしてココロ (2016)
  • Author(s): 塩田清二、竹ノ谷文子、亀井淳三 他
  • Total Pages: 83
  • Publisher: Biophilia
• [Book] アンチエイジング医学の基礎と臨床 (2015)
  • Author(s): 藤英胤（編集）、塩田清二、竹ノ谷文子 他
  • Total Pages: 447
  • Publisher: メジカルビュー社