New strategy for treatment of spinal cord injury by neuropeptide

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15670
• Research Institution: Hoshi University
• Principal Investigator: 塩田 清二 星薬科大学, 先端生命科学研究所, 教授 (80102375)
• Co-Investigator(Kenkyū-buntansha): 土肥 謙二 昭和大学, 医学部, 教授 (20301509) ; 中町 智哉 富山大学, 大学院理工学研究部(理学), 助教 (30433840)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: PACAP / 脊髄損傷 / 神経細胞死防御 / 神経再生

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る。
我々は、プロテオミクス解析により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により、CRMP2タンパク質（軸索伸長タンパク）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虚血巣領域の神経細胞に強く認められることをすでに論文で報告した。
本年度はより運動機能や軸索新生を評価し易いマウスの脊髄損傷モデルを用いた機能解析を行った。具体的にはカミソリを用いて脊髄を離断して損傷させたマウスにPACAPを浸み込ませた徐放性ゲルを損傷脊髄に塗布し、その後の運動機能を経時的に評価したところ、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２週間で有意な運動機能の回復が認められた。さらに損傷後の脊髄においてCRMP2 mRNA発現量を測定したところ、PACAP添加群では生理的食塩水添加群と比較して7日目で増加傾向を示し、14日目で有意差が認められた。CRMP2の発現は脊髄の大型及び小型の神経細胞と一部のオリゴデンドロサイトにみられ、さらに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。これはインパクターを用いた脊髄損傷モデル動物とほぼ同じ結果であり、異なる脊髄損傷モデルにおいても軸索伸長が起きたことが分かった。順行性蛍光トレーサーを損傷部位の上位の頸髄レベルに投与を行なって軸索伸長を蛍光顕微鏡を用いて検索した結果、PACAP添加群では損傷領域より下位における軸索再生が多数観察された。
以上の結果より、PACAPは損傷領域でCRMP2発現量を上昇させ、損傷後の軸索再生を誘導することにより運動機能の回復を促進することが明らかになった。

Research Products

• [Journal Article] Role of the autonomic nervous system in the tumor- micro-environment and its therapeutic potential. (2016)
  • Author(s): XU Z, SHIODA S, JINUSHI M, KAWAKAMI Y, OHTAKI H, WANG S, ZHAO X, LIU Y, ZHOU D, GUO Y.
  • Journal Title: Curr Pharm Des. Volume: 23 Pages: 1687-1692
  • DOI: 10.2174/1381612822666161025152942
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bihavioral and omics analyses study on potential involvement of dipeptide balenine through supplementation in diet of senescence-accelerated mouse prone 8. (2016)
  • Author(s): WADA N, YAMANAKA S, SHIOBATO J, RAKWAL R, HIRAKO S, IIZUKA Y, KIM H, MATSUMOTO A, KIMURA A, TAKENOYA F, YASUNAGA G, SHIODA S
  • Journal Title: Genom Data Volume: 10 Pages: 38-50
  • DOI: 10.1016/j.gdata.2016.09.04
  • Peer Reviewed
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide promotes eccrine gland sweat secretion. (2016)
  • Author(s): SASAKI S, WATANABE J, OHTAKI H, MATSUMOTO M, MURAI N, NAKAMACHI T, HANNIBAL J, FAHRENKLUG J, HASIMOTO H, WATANABE H, SUEKI H, HONDA K, MIYAZAKI A, SHIODA S
  • Journal Title: Br J Dermatol. Volume: 176 Pages: 413-422
  • DOI: 10.1111/bjd.14885
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PACAP suppresses dry eye signs by stimulating tear secretion. (2016)
  • Author(s): NAKAMACHI T, OHTAKI H, SEKI T, YOFU S, KAGAMI N, HASHIOMOTO H, SHINTANI N, BABA A, MARK L, LANEKOFF I, KISS P, FARKAS J, REGLODI D, SHIODA S
  • Journal Title: Nat Commun. Volume: 7 Pages: 12034
  • DOI: 10.1038/ncomms12034
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide enhances saliva secretion via direct binding to PACAP receptors of major salivary glands in mice. (2016)
  • Author(s): MATOBA Y, NONAKA N, TAKAGI Y, IMAMURA E, NARUKAWA M, NAKAMACHI T, SHIODA S, BANKS WA, NAKAMURA M.
  • Journal Title: Anat Rec (Hoboken). Volume: 299 Pages: 1293-1299
  • DOI: 10.1002/ar.23388
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Unlabeling the rat blood genome-wide transcriptome after oral administration of lavender oil by a two-color dye-swap DNA microarray approach. (2016)
  • Author(s): HORI M, KUBO H, SHIBATO J, SAITO T, OGAWA T, WAKAMORI M, MASUO Y, SHIODA S, RAKWAL R
  • Journal Title: Genom Data Volume: 8 Pages: 139-145
  • DOI: 10.1016/j.gdata.2016.05.005
  • Peer Reviewed
• [Journal Article] Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice. (2016)
  • Author(s): KAGEYAMA H, SHIBA K, HIRAKO S, WADA N, YAMANAKA S, NOGI Y, TAKENOYA F, NONAKA N, HIRAKO S, INOUE S, SHIODA S
  • Journal Title: Sci Rep. Volume: 6 Pages: 28200
  • DOI: 0.1038/srep28200
  • Peer Reviewed / Open Access
• [Journal Article] Fish and fenofibrate inhibit pancreatic islet hypertrophy and improve glucose and lipid dysfunctions with different ways in diabetic KK mice. (2016)
  • Author(s): NAKASATOMI M, KIM H, ARAI T, HIRAKO S, SHIODA S, IIZUKA Y, SAKURAI K, MATSUMOTO A.
  • Journal Title: Obes Res Clin Pract. Volume: - Pages: -
  • DOI: 10.1016/j.orcp.2016.03.012
  • Peer Reviewed
• [Journal Article] Narcolepsy-like sleep disturbance in orexin kcnokout 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: 233 Pages: 2343-2353
  • DOI: 10.1007/s00213-016-4282-1
  • Peer Reviewed
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide (PACAP) contiributes 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 involve 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: 59 Pages: 270-279
  • DOI: 10.1007/s12031-016-0731-x
  • Peer Reviewed
• [Journal Article] Autonomic nervous system-mediated effects of galanin-like peptide on lipid metabolism in liver and adipose tissue. (2016)
  • Author(s): HIRAKO S, WADA N, KAGEYAMA H, TAKENOYA F, IZUMIDA Y, KIM H, IIZUKA Y, MATSUMOTO A, OKABE M, KIMURA A, SUZUKI M, YAMANAKA S, SHIODA S
  • Journal Title: Sci Rep. Volume: 6 Pages: 21481
  • DOI: 10.1038/srep21481
  • Peer Reviewed / Open Access
• [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
  • Peer Reviewed
• [Journal Article] Hepatic lipid accumulation is ameliorated in obese KK miceby dietary sei whale oil. (2016)
  • Author(s): HIRAKO S, SUZUKI M, KIM H, IIZUKA Y, MATSUMOTO A, WADA N, OKABE M, TAKENOYA F, YASUNAGA G, YAMANAKA S, MIYAZAKI A, SHIODA S
  • Journal Title: Fish Sci. Volume: 82 Pages: 509-517
  • DOI: 10.1007/s12562-016-0971-2
  • Peer Reviewed
• [Journal Article] Pleiotropic and retinoprotective functions of PACAP. (2016)
  • Author(s): SHIODA S, TAKENOYA F, WADA N, HIRABAYASHI T, SEKI T, NAKAMACHI T
  • Journal Title: Anat Sci Int. Volume: 91 Pages: 313-324
  • DOI: 10.1007/s12565-016-0351-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autonomic nervous system-mediated effects of GALP on energy metabolism. (2016)
  • Author(s): HIRAKO S, WADA N, KAGEYAMA H, TAKENOYA F, INOUE S, SHIODA S
  • Journal Title: Nihon Yakurigaku Zasshi Volume: 148 Pages: 23-37
  • DOI: 10.1254/fpj.148.23
  • Peer Reviewed
• [Presentation] Neuroprotective effect of PACAP on spinal cord injury through CRMP-2 protein (2016)
  • Author(s): Shioda S
  • Organizer: REGPEP2016
  • Place of Presentation: Rouen, France
  • Year and Date: 2016-07-13 – 2016-07-13
  • Int'l Joint Research / Invited
• [Presentation] Neuroprotective and neurogenic effect of PACAP after stroke (2016)
  • Author(s): Nakamachi T, Shioda S
  • Organizer: Satellite Symposium of REGPEP2016
  • Place of Presentation: Rouen, France
  • Year and Date: 2016-07-12 – 2016-07-12
  • Int'l Joint Research / Invited
• [Presentation] 神経ペプチドPACAPの多彩な生理作用 (2016)
  • Author(s): 塩田清二
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 日本科学未来館（東京）
  • Year and Date: 2016-05-13 – 2016-05-13
  • Invited
• [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: 日本科学未来館（東京）
  • Year and Date: 2016-05-13 – 2016-05-13
• [Presentation] PACAPはアクアポリン5を介して涙液分泌を促進する (2016)
  • Author(s): 中町 智哉、大滝博和、関 保、渡邊 潤、塩田 清二
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 日本科学未来館（東京）
  • Year and Date: 2016-05-13 – 2016-05-13
• [Book] Pituitary Adenylate Cyclase Activating Polypeptide- Current Topics in Neurotoxicity 11. (2016)
  • Author(s): WATANABE J, SEKI T, SHIODA S
  • Total Pages: 840
  • Publisher: Springer
• [Book] Pituitary Adenylate Cyclase Activating Polypeptide- Current Topics in Neurotoxicity 11. (2016)
  • Author(s): OHTAKI H, SHIODA S
  • Total Pages: 840
  • Publisher: Springer
• [Patent(Industrial Property Rights)] バラ科サクラ属に属する植物の葉の抽出液を含有する抗腫瘍製剤 (2016)
  • Inventor(s): 塩田清二
  • Industrial Property Rights Holder: 塩田清二
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-130722
  • Filing Date: 2016-06-30
• [Patent(Industrial Property Rights)] 生物由来液取得方法 (2016)
  • Inventor(s): 塩田清二
  • Industrial Property Rights Holder: 塩田清二
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-130711
  • Filing Date: 2016-06-30