Drug development using novel animal model based on the pathogenesis of Parkinson' s disease-related disorders

• Project/Area Number: 20406005
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 海外学術
• Research Field: Drug development chemistry
• Research Institution: Hiroshima University
• Principal Investigator: OHTA Shigeru 広島大学, 大学院・医歯薬学総合研究科, 教授 (60160503)
• Co-Investigator(Kenkyū-buntansha): SUGIHARA Kazumi 広島国際大学, 薬学部, 准教授 (20271067)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2010: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2009: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2008: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 熱帯風土病 / パーキンソン病関連疾患 / イソキノリンアルカロイド / P糖タンパ / 地域特異的神経変性疾患 / トゲバンレイシ / P糖タンパク質 / カリブ諸島 / バーキンソン病類縁疾患 / テトラヒドロイソキノリン / 天然物化学 / 構造決定 / アルカロイド / パーキンソン病モデル動物 / 神経毒

Research Abstract

We identified the structures of about 10 compounds in Annona muricata, which is a candidate for environmental factors involved in the pathogenesis of Parkinson' s disease-related disorders. Among them, a tetrahydroisoquinoline derivative induced an abnormal accumulation of some proteins and endoplasmic reticulum stress.

Research Products

• [Journal Article] Annonamine, anew aporphine alkaloid from the leaves ofAnnona muricata (2012)
  • Author(s): Matsushige A, Kotake Y, Matsunami K, Otsuka H, Ohta S, Takeda Y.
  • Journal Title: Chem Pharm Bull Volume: 60 Pages: 257-259
  • Peer Reviewed
• [Journal Article] Three new megastigmanes from the leaves of Annona muricata (2012)
  • Author(s): Matsushige A, Matsunami K, Kotake Y, Otsuka H, Ohta S.
  • Journal Title: J NatMed Volume: 66 Pages: 284-291
  • Peer Reviewed
• [Journal Article] Proteindisulfide isomerase knockdown-inducedcell death is cell-line-dependent andinvolves apoptosis in MCF-7 cells (2011)
  • Author(s): Hashida T, Kotake Y, Ohta S.
  • Journal Title: JToxicol Sci Volume: 6 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Effect oftea beverages on aldehyde oxidase activity (2011)
  • Author(s): Tayama Y, Sugihara K, Sanoh S, MiyakeK, Morita S, Kitamura S, Ohta S.
  • Journal Title: Drug Metab Pharmacokinet Volume: 26 Pages: 94-101
  • Peer Reviewed
• [Journal Article] Effect of tea beverages on aldehyde oxidase activity (2011)
  • Author(s): Tayama, et al.
  • Journal Title: Drug Metab.Pharmacokinet. Volume: 26 Pages: 94-101
  • Peer Reviewed
• [Journal Article] Ipso substitution of bisphenol A catalyzed by microsomal cytochrome P450 and enhancement of estrogenic activity (2011)
  • Author(s): Nakamura, et al.
  • Journal Title: Toxicol.Lett. Volume: 203 Pages: 92-95
  • Peer Reviewed
• [Journal Article] Design, synthesis, and pharmacological activity of nonallergenic pyrazolone-type antipyretic analgesics (2010)
  • Author(s): Uramaru N, Shigematsu H, Toda A, Eyanagi R, Kitamura S, Ohta S.
  • Journal Title: J Med Chem Volume: 53 Pages: 8727-8733
  • Peer Reviewed
• [Journal Article] Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity : a comparative study in humans and rodents including chimeric mice carrying human liver (2010)
  • Author(s): Nurrochmad A, Ishii Y, Nakanoh H, InoueT, Horie T, Sugihara K, Ohta S, Taketomi A, Maehara Y, Yamada H.
  • Journal Title: Drug MetabPharmacokinet Volume: 25 Pages: 262-273
  • NAID: 10027582853
  • Peer Reviewed
• [Journal Article] Design and synthesis of androgen receptorfull antagonists bearing a p-carboranecage : promising ligands for anti-and rogen with drawal syndrome (2010)
  • Author(s): Goto T, Ohta K, Fujii S, Ohta S, Endo Y
  • Journal Title: J Med Chem Volume: 53 Pages: 4917-4926
  • Peer Reviewed
• [Journal Article] Involvement of autophagy via mammaliantarget of rapamycin(mTOR) inhibition intributyltin-induced neuronal cell death (2010)
  • Author(s): Nakatsu Y, Kotake Y, Takai N, Ohta S.
  • Journal Title: JToxicol Sci Volume: 35 Pages: 245-251
  • Peer Reviewed
• [Journal Article] 1-Benzyl-1, 2, 3, 4-tetrahydroisoquinolinebinds with tubulin beta, a substrate of parkin, and reduces its polyubiquitination (2010)
  • Author(s): Kohta R, Kotake Y, Hosoya T, HiramatsuT, Otsubo Y, Koyama H, Hirokane Y, YokoyamaY, Ikeshoji H, Oofusa K, Suzuki M, Ohta S.
  • Journal Title: J Neurochem Volume: 114 Pages: 1291-1301
  • Peer Reviewed
• [Journal Article] Approach for invivo protein binding of 5-n-butylpyrazolo[ 1, 5-a] pyrimidine bioactivated in chimeric mice with humanized liver bytwo-dimensional electrophoresis with accelerator mass spectrometry (2010)
  • Author(s): Yamazaki H, Kuribayashi S, Inoue T, Tateno C, Nishikura Y, Oofusa K, Harada D, Naito S, Horie T, Ohta S.
  • Journal Title: Chem ResToxicol Volume: 23 Pages: 152-158
  • Peer Reviewed
• [Journal Article] 1-Benzyl-1,2,3,4-tetrahydroisoquinoline binds with tubulin beta, a substrate of parkin, and reduces its polyubiquitination (2010)
  • Author(s): Kohta, et al.
  • Journal Title: J.Neurochem. Volume: 114 Pages: 1291-1301
  • Peer Reviewed
• [Journal Article] Involvement of autophagy via mammalian target of rapamycin (mTOR) inhibition in tributyltin-induced neuronal cell death (2010)
  • Author(s): Nakatsu, et al.
  • Journal Title: J.Toxicol.Sci. Volume: 35 Pages: 245-251
  • Peer Reviewed
• [Journal Article] Design and synthesis of androgen receptor full antagonists bearing a p-carborane cage : promising ligands for anti-androgen withdrawal syndrome (2010)
  • Author(s): Goto, et al.
  • Journal Title: J.Med.Chem. Volume: 53 Pages: 4917-4926
  • Peer Reviewed
• [Journal Article] Activation of morphine glucuronidation by fatty acyl-CoAs and its plasticity : a comparative study in humans and rodents including chimeric mice carrying human liver (2010)
  • Author(s): Nurrochmad, et al.
  • Journal Title: Drug Metab.Pharmacokinet. Volume: 25 Pages: 262-273
  • Peer Reviewed
• [Journal Article] Design, synthesis, and pharmacological activity of nonallergenic pyrazolone-type antipyretic analgesics (2010)
  • Author(s): Uramaru, et al.
  • Journal Title: J.Med.Chem. Volume: 53 Pages: 8727-8733
  • Peer Reviewed
• [Journal Article] Protein disulfide isomerase knockdown-induced cell death is cell-line-dependent and involves apoptosis in MCF-7 cells (2010)
  • Author(s): Hashida, et al.
  • Journal Title: J.Toxicol.Sci. Volume: 36 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Novel estrogen receptor(ER) modulators : carbamate and thiocarbamate derivatives with m-carborane bisphenolstructure (2009)
  • Author(s): Ohta K, Ogawa T, Suzuki T, Ohta S, EndoY.
  • Journal Title: Bioorg Med Chem Volume: 17 Pages: 7958-7963
  • Peer Reviewed
• [Journal Article] Identification of rat prostaticse creted proteins using mass spectrometricanalysis and androgen-dependent mRNAexpression (2009)
  • Author(s): Fujimoto N, Suzuki T, Ohta S, KitamuraS.
  • Journal Title: J Androl Volume: 30 Pages: 669-678
  • Peer Reviewed
• [Journal Article] Prediction of humandisposition toward S-3H-warfarin usingchimeric mice with humanized liver (2009)
  • Author(s): Inoue T, Sugihara K, Ohshita H, HorieT, Kitamura S, Ohta S.
  • Journal Title: DrugMetab Pharmacokinet Volume: 24 Pages: 153-160
  • Peer Reviewed
• [Journal Article] Current situation of drug in for mation in the kindergarten andnursery teacher : a pilot study (2009)
  • Author(s): Tayama Y, Miyake K, Kanazawa E, KanekoT, Sugihara K, Toyomi A, Morita S, Kobayashi M, Ohta S.
  • Journal Title: YakugakuZasshi Volume: 129 Pages: 617-622
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of p-carborane bisphenols andtheir derivatives : structure-activityre lationship for estrogenic activity (2009)
  • Author(s): Ogawa T, Ohta K, Iijima T, Suzuki T, Ohta S, Endo Y.
  • Journal Title: Bioorg Med Chem Volume: 17 Pages: 1109-1117
  • Peer Reviewed
• [Journal Article] Long-term exposure to endogenous levels of tributyltin decreases GluR2 expression and increases neuronal vulnerability to glutamate. (2009)
  • Author(s): Nakatsu, et al.
  • Journal Title: Toxicol.Appl.Pharmacol. Volume: 240 Pages: 292-298
  • Peer Reviewed
• [Journal Article] Current situation of drug information in the kindergarten and nursery teacher : a pilot study. (2009)
  • Author(s): Tayama, et al.
  • Journal Title: Yakugakuzasshi Volume: 129 Pages: 617-622
  • Peer Reviewed
• [Journal Article] Prediction of human disposition toward S-3H-warfarin using chimeric mice with humanized liver. (2009)
  • Author(s): Inoue, et al.
  • Journal Title: Drug Metab.Pharmacokinet. Volume: 24 Pages: 153-160
  • Peer Reviewed
• [Journal Article] Identification of rat prostatic secreted proteins using mass spectrometric analysis and androgen-dependent mRNA expression. (2009)
  • Author(s): Fujimoto, et al.
  • Journal Title: J.Androl. Volume: 30 Pages: 669-678
  • Peer Reviewed
• [Journal Article] Modulation of connexin 43 in rotenone-induced model of Parkinson's disease (2009)
  • Author(s): Kawasaki, et al.
  • Journal Title: Neuroscience (in press)
  • Peer Reviewed
• [Journal Article] Long-term exposure to endogenous levelsof tributyltin decreases GluR2 expressionand increases neuronal vulnerability toglutamate (2008)
  • Author(s): Nakatsu Y, Kotake Y, Takishita T, OhtaS.
  • Journal Title: Toxicol Appl Pharmacol Volume: 240 Pages: 292-298
  • Peer Reviewed
• [Journal Article] CYP2C9-catalyzedmetabolism of S-warfarin to 7-hydroxywarfarinin vivo and in vitro in chimericmice with humanized liver (2008)
  • Author(s): Inoue T, Nitta K, Sugihara K, Horie T, Kitamura S, Ohta S.
  • Journal Title: Drug MetabDispos Volume: 36 Pages: 2429-2433
  • Peer Reviewed
• [Journal Article] Design and synthesis ofcarborane-containing androgen receptor(AR) antagonist bearing a pyridine ring (2008)
  • Author(s): Ohta K, Goto T, Fijii S, Suzuki T, OhtaS, Endo Y.
  • Journal Title: Bioorg Med Chem Volume: 16 Pages: 8022-8028
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated proteinkinase by tributyltin induces neuronalcell death (2008)
  • Author(s): Nakatsu Y, Kotake Y, Hino A, Ohta S.
  • Journal Title: Toxicol Appl Pharmacol Volume: 230 Pages: 358-363
  • Peer Reviewed
• [Journal Article] Aldehyde oxidase-catalyzed metabolism ofN1-methylnicotinamide in vivo and in vitroin chimeric mice with humanized liver (2008)
  • Author(s): Kitamura S, Nitta K, Tayama Y, TanoueC, Sugihara K, Inoue T, Horie T, Ohta S.
  • Journal Title: Drug Metab Dispos Volume: 36 Pages: 1202-1205
  • Peer Reviewed
• [Journal Article] Activation of AMP-activated protein kinase by tributylt in induces neuronal cell death. (2008)
  • Author(s): Naka tsu, et al.
  • Journal Title: Toxicology and Applied Pharmacology 230 Pages: 358-363
  • Peer Reviewed
• [Presentation] パーキンソン病発症原因について (2010)
  • Author(s): 太田茂
  • Organizer: 筑波大学講演会(招待講演)
  • Place of Presentation: つくば
  • Year and Date: 2010-11-10
• [Presentation] パーキンソン病発症原因について (2010)
  • Author(s): 太田茂
  • Organizer: 筑波大学講演会
  • Place of Presentation: つくば(招待講演)
  • Year and Date: 2010-11-10
• [Presentation] パーキンソン病関連神経毒MPP+によるparkin活性阻害と基質タンパク質tubulinの蓄積 (2010)
  • Author(s): 廣兼裕司他
  • Organizer: 第49回日本薬学会中国四国支部学術大会
  • Place of Presentation: 米子
  • Year and Date: 2010-11-06
• [Presentation] トゲバンレイシ含有tetrahydroisoquinoline誘導体の神経細胞毒性 (2010)
  • Author(s): 松重彩乃他
  • Organizer: 第49回日本薬学会中国四国支部学術大会
  • Place of Presentation: 米子
  • Year and Date: 2010-11-06
• [Presentation] カテコール骨格を有するパーキンソン病関連神経毒がユビキチンE3リガーゼparkinに与える影響 (2010)
  • Author(s): 佐溝茂良他
  • Organizer: フォーラム2010衛生薬学・環境トキシコロジー
  • Place of Presentation: 東京
  • Year and Date: 2010-09-09
• [Presentation] パーキンソン病関連神経毒はParkinに影響を与え、小胞体ストレスを誘発する (2010)
  • Author(s): 佐溝茂良他
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-30
• [Presentation] 家族性パーキンソン病原因タンパクParkinに対する1BnTIQの影響 (2010)
  • Author(s): 廣兼裕司他
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-30
• [Presentation] トゲバンレイシ葉部に含まれるアルカロイド成分の探索研究 (2010)
  • Author(s): 松重彩乃他
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] パーキンソン病発症機構の解明に向けて (2010)
  • Author(s): 太田茂
  • Organizer: 平成21年度北陸大学学術フロンティア年次研究集会・総括集会(招待講演)
  • Place of Presentation: 金沢
  • Year and Date: 2010-03-16
• [Presentation] パーキンソン病発症解明にむけて (2010)
  • Author(s): 太田茂
  • Organizer: 北陸大学学術フロンティア総括集会
  • Place of Presentation: 金沢
  • Year and Date: 2010-03-16
• [Presentation] α-synucleinオリゴマー化に対するパーキンソン病関連神経毒の影響 (2009)
  • Author(s): 山脇裕一郎他
  • Organizer: 第48回日本薬学会中国四国支部会学術大会
  • Place of Presentation: 徳島
  • Year and Date: 2009-11-07
• [Presentation] パーキンソン病関連脳内在性アミンTIQ誘導体の小胞体ストレス誘発作用 (2009)
  • Author(s): 佐溝茂良他
  • Organizer: フォーラム2009衛生薬学・環境トキシコロジー
  • Place of Presentation: 沖縄
  • Year and Date: 2009-11-06
• [Presentation] パーキンソン病関連神経毒によるParkinタンパク質の不溶化および不活性化 (2009)
  • Author(s): 廣兼裕司他
  • Organizer: フォーラム2009衛生薬学・環境トキシコロジー
  • Place of Presentation: 沖縄
  • Year and Date: 2009-11-06
• [Presentation] パーキンソン病関連神経毒によるtubulin結合タンパク質α-synucleinのオリゴマー化 (2009)
  • Author(s): 山脇裕一郎他
  • Organizer: フォーラム2009衛生薬学・環境トキシコロジー
  • Place of Presentation: 沖縄
  • Year and Date: 2009-11-06
• [Presentation] トゲバンレイシ葉に含まれる神経毒性化合物の探索 (2009)
  • Author(s): 松重彩乃, ら
  • Organizer: フォーラム2009衛生薬学・環境トキシコロジー
  • Place of Presentation: 沖縄
  • Year and Date: 2009-11-05
• [Presentation] パーキンソン病発症機構の分子メカニズム (2009)
  • Author(s): 太田茂
  • Organizer: 鳥取パーキンソン病症例検討会(招待講演)
  • Place of Presentation: 鳥取
  • Year and Date: 2009-07-10
• [Presentation] Rotenoneにより引き起こされるastrocyte gap junctions/hemichannelsの変動(in vivo, in vitro) (2008)
  • Author(s): 河寄麻実, et al.
  • Organizer: 第51回日本神経化学会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-13