Development of a drug, which can pass the blood-brain barrier and induces neuroprotective proteins in the brain.

• Project/Area Number: 15590925
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY
• Principal Investigator: MARUYAMA Wakako National Center for Geriatrics and Gerontology, Department of Geriatric Medicine, Head, 老年病研究部, 部長 (20333396)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Neuroprotective drug / Neurotrophic factor / Parkinson's disease / Alzheimer's disease / Propargylamine / Transcription factor / Cerebrospinal fluid / Japanese monkey / BCL-2 / NFκB / プロパルジルアミン / モノアミンオキシダーゼ

Research Abstract

Propargylamine derivatives such as (-)deprenyl [selegiline] and rasagiline are developed as the selective inhibitors of type B monoamine oxidase (MAO-B). Among them, setegilie has been used clinicaly for the treatment of Parkinson's disease for MAO-B inhbitors expecting to increase neurotransmitter dopamine. The neuroprotective effects of protargylamines which is independent to enzyme inhibition have been reported by in vtro and in vivo experiments, but the molecular mechanism has not been elucidated. Using clonal neuroblastoma SH-SY5Y cells, apoptosis model was estabished and it was found that propargylamines protected the cells from mitchondria-dependent cell death by activating stress-responsible transcription factors such as NFkappaB. NFkappaB induced neuroprotective proteins such as neurotrophic fectors, BDNF and GDNF, BCL-2 and SOD. The neuroprotective effect of propargylamines may be ascribed to the induction of new proteins and the clinical effects of these drugs should be re-examined in concern wih this aspect. Neurotrophic factors are known to be secreted from the cells and their level in the cerebrospinal fluid(CSF) may correlate wih that in the brain. We admhistrated rasagiline [N-propargyl-1(R)-aminoindane] or saline to 4 Japanese monkeys respectively, and CSF was obtained once a week up to 8 weeks. Sight and transient increase of BDNF was observed but the difference was not marked. The further study to estimate optimum dose and period of the drugs to increase neuroprotective proteins is needed.

Research Products

• [Journal Article] Rasagiline : Neurodegeneration, neuroprotection, and mitochondrial Permeability transition. (2005)
  • Author(s): Youdim MBH, Bar Am O, Yogev-Falach M, Weinreb O, Maruyama W, Naoi M.Am
  • Journal Title: J.Neurosci.Res 79 Pages: 172-179
• [Journal Article] Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase in hibitors : Occurrence, meta- bolism and function in human brains. (2004)
  • Author(s): Naoi M, Maruyama W, Nagy GM
  • Journal Title: NeuroToxicology 25 Pages: 193-204
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neuroprotective function of R-(-)-(benzyofuran-2-yl) -2-propylamino-pentane, [R-(-)-BPAP], against apoptosis induced by N-methyl(R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells. (2004)
  • Author(s): Maruyama W, Yi H, Takahashi T, Shimazu S, Ohde H, Yoneda K, Iwasa K, Naoi M.
  • Journal Title: Life Sci. 21 Pages: 107-117
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] N-Propargyl-1(R)-aminoindan, rasagiline, increases glial cell line- derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. (2004)
  • Author(s): Maruyama W, Nitta A, Shamoto-Nagai M, Hirata Y, Akao Y, Youdim M, Furukawa S, Nabeshima T, Naoi M.
  • Journal Title: Neurochem.Int. 25 Pages: 193-204
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dopamine-derived salsolinol derivatives as endogenous monoaraine oxidase inhibitors : Occurrence, metabolism and function in human brains. (2004)
  • Author(s): M.Naoi, W.Maruyama, G.M.Nagy
  • Journal Title: Neuro Toxicology 25 Pages: 193-204
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuroprotective function of R-(-)-(benzyofuran-2-yl)-2-propylatnino-pentane, R-(-)-BPAP], against apoptosis induced by N-methyl (R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoraa SH-SY5Y cells. (2004)
  • Author(s): W.Maruyama, H.Yi, T.Takahashi, S.Shimazu, H.Ohde, K.Yoneda, K.Iwasa, M.Naoi
  • Journal Title: Life Sci. 21 Pages: 107-117
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] N-Propargyl-1(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor(GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kB transcription factor. (2004)
  • Author(s): W.Maruyama, A.Nitta, M.Shamoto-Nagai, Y.Hirata, Y.Akao, S.Furukawa, T.Nabeshima, M.Naoi
  • Journal Title: Neurochem.Int. 25 Pages: 193-204
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dopamine-derived salsolinol derivatives as endogenous monoamioxidase inhibitors : Occurrence, meta- bolism and function (2004)
  • Author(s): Naoi M, Maruyama W, Nagy GM
  • Journal Title: NeuroToxicol. 25 Pages: 193-204
• [Journal Article] N-Propargyl-1(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Ycells through activation of NF-kappaB transcription factor. (2004)
  • Author(s): Maruyama W, Nitta A, Shamoto-Nagai M, Hirata Y, Akao Y, Youdim M, Furukawa S, Nabeshima T, Naoi M.
  • Journal Title: Neurochem.Int. 44 Pages: 393-400
• [Journal Article] Neuroprotective function of R-(-)-(benzyofuran-2-yl)-2-propylamino-pentane, [R-(-)- BPAP], against apoptosis induced by N-methyl(R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells. (2004)
  • Author(s): Maruyama W, Yi H, Takahashi T, Shimazu S, Ohde H, Yoneda K, Iwasa K, Naoi M.
  • Journal Title: Life Sci. 75 Pages: 107-117
• [Journal Article] Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells. (2004)
  • Author(s): Shamoto-Nagai M, Maruyama W, Akao Y, Osawa T, Tribl F, Gerlach M, Zucca FA, Zecca L, Riederer P, Naoi M.
  • Journal Title: J.Neural Transm. 111 Pages: 1253-1265
• [Journal Article] A highly bioactive lignophenol derivative from bamboo lignin exhibits a potent activity to suppress apoptosis induced by oxidative stress in human neurobalstoma SH-SY5Y cells. (2004)
  • Author(s): Akao Y, Seki N, Nakagawa Y, Yi H, Matsumoto K, Ito Y, Ito K, Funaoka M, Maruyama W, Naoi M, Nozawa Y.
  • Journal Title: Bioorg.Med.Chem. 12 Pages: 4794-4801
• [Journal Article] Anti-apoptotic function of propargylamine inhibitors of type-B -monoamine oxidase. (2003)
  • Author(s): Naoi M, Maruyama W, M.B.H.Youdim, P.Yu, A.A.Boulton.
  • Journal Title: Inflammopharmacology 11 Pages: 175-181
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. (2003)
  • Author(s): Shamoto-Nagai M, Maruyama W, Kato Y, Isobe K, Tanaka M, Naoi M, Osawa T.
  • Journal Title: J.Neurosci.Res. 74 Pages: 589-597
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Essentiality of bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroproective-antiapoptotic action of the anti-Parkinson drug, rasagiline. (2003)
  • Author(s): MB H.Youdim, T Amit, M.Falach-Yogev, OB.Am, Maruyama W, Naoi M.
  • Journal Title: Biochem.Pharmacol. 66 Pages: 1635-1641
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor (2003)
  • Author(s): Maruyama W, M.Weinstock, MBH Youdim, Nagai M, Naoi M.
  • Journal Title: Neurosci.Lett. 341(3) Pages: 233-236
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Anti-apoptotic function of propargylamine inhibitors of type-B-monoamine oxidase. (2003)
  • Author(s): M.Naoi, W.Maruyama, M.B.H.Youdira, P.Yu, A.A.Boulton
  • Journal Title: Inflammopharmacology 11 Pages: 175-181
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells. (2003)
  • Author(s): M.Shamoto-Nagai, W.Maruyama, Y.Kato, K.Isobe, M.Tanaka, M.Naoi, T.Osawa
  • Journal Title: J.Neurosci.Res. 74 Pages: 589-597
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The Essentiality of bcl-2,PKC and proteasome-ubiquitin complex activations in the neuroproective-antiapoptotic action of the anti-Parkinson drug, rasagiline. (2003)
  • Author(s): MB H.Youdira, T Amit, M.Falach-Yogev, OB.Am, W.Maruyama, M.Naoi:
  • Journal Title: Biochem.Pharmacol. 66 Pages: 1635-1641
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. (2003)
  • Author(s): W.Maruyama, M.Weinstock, MBH Youdim, M.Nagai, M.Naoi
  • Journal Title: Neurosci.Lett. 341(3) Pages: 233-236
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mitochondrial Genome Variation in Eastern Asia and the Peopling of Japan.
  • Author(s): Tanaka M, V.M.Cabrera, A.M.Gonzalez, J.M.Larruga, Takeyasu T, Fuku N, L-J.Guo, Hirose R, Fujita Y, Kurata M, Shinoda K, Umetsu K, Yamada Y, Oshida Y, Sato Y, Hattori N, Mizuno Y, Arai Y, Hirose N, Ohta S, Ogawa O, Tanaka Y, Kawamori R, Shamoto-Nagai M, Maruyama W, Shimokata H, Suzuki R, Shimodaira H.
  • Journal Title: Genome Res. In press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mitochondrial Genome Variation in Eastern Asia and the Peopling of Japan.
  • Author(s): M.Tanaka, V.M.Cabrera, A.M.Gonzalez, J.M.Larruga, T.Takeyasu, N.Fuku, L-J.Guo, R.Hirose, Y.Fujita, M.Kurata, K.Shinoda, K.Umetsu, Y.Yamada, Y.Oshida, Y.Sato, N.Hattori, Y.Mizuno, Y.Arai, N.Hirose, S.Ohta, O.Ogawa, Y.Tanaka, R.Kawamori, M.Shamoto-Nagai, W.Maruyama, H.Shimokata, R.Suzuki, H.Shimodaira
  • Journal Title: Genome Res. (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Monoamine oxidase and the inhibitors : Involvement in cell death and survival of neurons.
  • Author(s): M.Naoi, W.Maruyama
  • Journal Title: Milestones in monoamine research. (I Lorok Tl (ed))(Medicina Publishing House, Budapest) (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidative stress in mitochondrial : The involvement in neurodegene-ative diseases.
  • Author(s): M.Naoi, W.Maruyama, M.Shamoto-Nagai, Y.Kato, M.Tanaka
  • Journal Title: The involvement in neurodegeneative diseases. Inflammation and Health(Surh Y-J. (ed)) (Mercel Dekker, New York, Oxidative Stress) (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuroprotection by rasagiline, N-propargyl-1R(+)-aminoindan, and related propargylamines is mediated by suppression of mitochondrial death signal and induction of anti-apoptotic genes.
  • Author(s): W.Maruyama, Y.Akao, A.Nitta, M.Naoi
  • Journal Title: Inflammation and Health(Surh Y-J. (ed)) (Mercel Dekker, New York, Oxidative Stress) (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Oxidative Stress, Inflammation and Health (2005)
  • Author(s): Maruyama W, Akao Y, Nitta A, Naoi M.
  • Total Pages: 240
• [Book] Oxidative Stress, Inflammation and Health (2005)
  • Author(s): Naoi M, Maruyama W, Shamoto-Nagai M, Kato Y, Tanaka M.
  • Total Pages: 240
• [Book] Mercel Dekker, New York, Oxidative Stress, Inflammation and Health(Surh Y-J. (ed)) (2004)
  • Author(s): Naoi M, Maruyama W, Shamoto-Nagai M, Kato Y, Tanaka M.
  • Total Pages: 240
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Mercel Dekker, New York, Oxidative Stress, Inflammation and Health(Surh Y-J. (ed)) (2004)
  • Author(s): Maruyama W, Akao Y, Nitta A, Naoi M.
  • Total Pages: 240
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 神経保護薬 (2004)
  • Author(s): 丸山和佳子, 直井信
  • Total Pages: 165
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Parkinson病の発症機序-Up date (2004)
  • Author(s): 丸山和佳子, 直井信
  • Total Pages: 110
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Monoamine Oxidase inhibitors and their role in neurotransmission (2004)
  • Author(s): Naoi M, Maruyama W.
  • Total Pages: 403
• [Book] 神経毒によるパーキンソン病モデル:細胞死機序の解明と神経保護薬の開発 (2004)
  • Author(s): 直井信, 丸山和佳子
  • Total Pages: 575
• [Book] 神経保護薬 (2004)
  • Author(s): 丸山和佳子, 直井信
  • Total Pages: 800
• [Book] Parkinson病の発症機序-Up date (2004)
  • Author(s): 丸山和佳子, 直井信
  • Total Pages: 122
• [Book] Medicina Publishing House, Budapest, Milestones in monoamine resarch.(Lorok Tl (ed)) (2003)
  • Author(s): Naoi M, Maruyama W.
  • Total Pages: 420
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 孤発性パーキンソン病の病因 (2003)
  • Author(s): 丸山和佳子, 直井信
  • Total Pages: 110
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] W.Maruyama, H.Yi, T.Takahashi, S.Shimazu, H.Ohde, K.Yoneda, K.Iwasa, M.Naoi: "Neuroprotective function of R-(-)-(benzyofuran-2-yl)-2-propylamino-pentane,[R-(-)-BPAP],against apoptosis induced by N-methyl(R)salsolinol, and endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells."Life Sci.. 印刷中.
• [Publications] M.Naoi, W.Maruyama, G.M.Nagy: "Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors : Occurrence, metabolism and function in human brains."NeuroToxicol.. 25. 193-204 (2004)
• [Publications] W.Maruyama, A.Nitta, M.Shamoto-Nagai, Y.Hirata, Y.Akao, S.Furukawa, T.Nabeshima, M.Naoi: "N-Propargyl-1(R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation NF-κB transcription factor."Neurochem.. 44(6). 393-400 (2004)
• [Publications] M.Shamoto-Nagai, W.Maruyama, Y.Kato, K.Isobe, M.Tanaka, M.Naoi, T.Osawa: "An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH-SY5Y cells."J.Neurosci.Res.. 74. 589-597 (2003)
• [Publications] MB H.Youdim, T Amit, M.Falach-Yogev, OB.Am, W.Maruyama, M.Naoi: "The Essentiality of bcl-2,PKC and proteasome-ubiquitin complex activations in the neuroproective-antiapoptotic action of the anti-Parkinson drug, rasagiline."Biochem.Pharmacol.. 66. 1635-1641 (2003)
• [Publications] W.Maruyama, M.Weinstock, MBH Youdim, M.Nagai, M.Naoi: "Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor."Neurosci.Lett.. 341(3). 233-236 (2003)
• [Publications] M.Naoi, W.Maruyama, M.B.H.Youdim, P.Yu, A.A.Boulton: "Inflammopharmacology"VSP Press. 251 (2003)
• [Publications] M.Naoi, W.Maruyama, Y.Kato, M.Shamoto-Nagai, M.Tanaka: "Oxidative Stress, Inflammation and Health(Y.-J.Surh (eds))"Marcel Dekker Inc(印刷中).
• [Publications] W.Maruyama, Y.Akao, A.Nitta, M.Naoi: "Oxidative Stress, Inflammation and Health(Y.-J.Surh (eds))"Marcel Dekker Inc(印刷中).
• [Publications] 直井信, 丸山和佳子: "脳の科学"200 (2004)
• [Publications] 丸山和佳子, 直井信: "内科"株式会社 南江堂. 198 (2004)
• [Publications] 丸山和佳子, 直井信: "医学のあゆみ"医歯薬出版社. 119 (2004)
• [Publications] 丸山和佳子, 直井信: "Prog.Med"ライフサイエンス.メディカ. 247 (2003)
• [Publications] 丸山和佳子, 直井信: "遺伝子医学"株式会社 メディカルドゥ. 150 (2003)