1994 Fiscal Year Annual Research Report

イソキノリンによるパーキンソン病モデルの作成

Research Project

Project/Area Number	06272212
Research Institution	Nagoya Institute of Technology
Principal Investigator	直井信名古屋工業大学, 工学部, 教授 (50022786)
Keywords	パーキンソン病 / 内在性神経毒 / ドパミン / 動物モデル / N-メチルイソキノリン / 酸化的ストレス
Research Abstract	ヒト脳に内在しドパミンより生合成される6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (DHTIQ)類をもちいパーキンソン病(PD)の動物モデルを作成した。ラット線状体にDHTIQ類を注入した所,1(R),2(N)-dimethy16,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl(R) salsolinol]のみが寡動,筋硬直などのPDの症状に類似の行動の異常を誘導した。こののPDモデルでの生化学的、病理学的な所見は黒質でのチロシン水酸化酵素の低下と抗同酵素免疫陽性細胞の選択的な減少を示した.またラット線状体と黒質でのDHTIQの蓄積の有無を検討したところ、NM(R)salsolinolから自動酸化により生成する1,2-dimethyl-6,7-dihydroxyisoquinolinium ion(1,2-DiMeDHIQ+)がその還元体より高濃度に黒質で蓄積していた。この機序をヒト神経芽細胞SH-SY5Yで検討したところ,NM(R)salsolinolのみがドパミンの輸送機関により取り込まれ。また細胞毒性は1,2-DiMeDHIQ+がより強力であった。これらの結果はNM(R)salsolinolが線状体から選択的に取り込まれ逆向性に軸索輸送され1,2-DiMeDHIQ+として蓄積され細胞毒性を示すことが明らかとなった。神経毒によるドパミン神経細胞死の機序を明かとするため、in vivo microdialysisを用い、脳内でのラジカル生成に対する神経毒の影響を検討した。DHTIQのうちMN(R)salsolinolのみが水酸化ラジカルを生成することを発見した。これらの結果からヒト脳でのDHTIQの分析を行ないパーキンソン病患者で増加しているかを検討をしている。

Research Products

(25 results)

All Other

All Publications (25 results)

[Publications] Maruyama,W.: "N-Methyl(R)salsolinol produced hydroxyl radicals;Involvement to neurotoxicty." Free Radical Biology & Medicine. (印刷中). (1995)
[Publications] Maruyama,W.: "Dopamine-derived 1-methyl-6,7-dihydroxyisoquinolines as hydroxyl radical promoters and scavengers in the rat brain:In vivo and in vitro studies." Journal of Neurochemisitry. (印刷中). (1995)
[Publications] Takahashi,T.: "Uptake of a neurotoxin-candidate,(R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system." Journal of Neural Transmission [GenSect]. 98. 107-118 (1994)
[Publications] Naoi,M.: "Inhibition of type A monoamine oxidase by 2(N)-methyl-6,7-dihydroxyisoquinoliniun ions." Neurochemistry International. 25. 991-995 (1994)
[Publications] 丸山和佳子: "Droxydopaのヒト体内における代謝の検討" 臨床神経学. 34. 991-995 (1994)
[Publications] 丸山和佳子: "Droxydopa(L-threo-3,4-dihyroxyphenylserine)のヒト脳内モノアミン代謝におよぼす影響" 臨床神経学. 34. 985-990 (1994)
[Publications] Matsubara,K.: "Structural studies of condensationproducts of biogenic amines as inhibitors of tryptophan hydroxylase." Brain Research. 655. 121-127 (1994)
[Publications] Naoi,M.: "Binding of 1,2(N)-dimethyl-6,7-digyfroxy-isoquinolinium ion to melanin;effects of ferrous and ferric ion on the binding." Neuroscience Letters. 171. 9-12 (1994)
[Publications] Naoi,M.: "Inhibition of tryptophan hyddroxylase by dopamine and the precursor amino acids." Biochemical Pharmacology. 48. 207-212 (1994)
[Publications] Maruyama,W.: "A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine,a precursor amino acid of norepinephrine,in the brain;Studies by in vivo microdialysis." Journal of Neural Transmission [P-D Sect]. 7. 21-33 (1994)
[Publications] Nakahara,D.: "Characterization of the in vivo action of (R)salsolinol,an endogenous metabolire by-product of alcohol,on serotonin and dopamine metabolism:A microdialysis study." Brain Research. 644. 226-233 (1994)
[Publications] Maruyama,W.: "Inhibition of tyrosine hydroxylase by a dopamine neurotoxin,1-methyl-4-phenylpyridini-um ion;depletion of allostery to the biopterin cofactor." Life Sciences. 55. 207-212 (1994)
[Publications] Kajita,M.: "Endogenous synthesis of N-methyl-norsalsolinol in rat brain during in vivo microdialysis with epinine." Journal of Chromatography B. 654. 263-269 (1994)
[Publications] Hattori,S.: "Striatal dopamine turnover during treadmill running in the rat:Relation to the speed of running." Brain Research Bulletin. 35. 41-49 (1994)
[Publications] 丸山和佳子: "脳内在性Catecholisoquinolinesによるパーキンソン病ラットモデルの作成" 神経化学. 53. 268-269 (1994)
[Publications] Naoi,M.: "Novel toxins and Parkinson's disease:N-methylation and oxidation as metabolic bioactivation as metabolic activation of neurotoxin" Journal of Neural Transmission,Suppliment. 41. 197-205 (1994)
[Publications] Maruyama,W.: "Food-derived heterocyclic amines,3-amino-1,4-dimethyl-5H-pyrid[4,3-b] indol and related amines,as inhibitiors of monoamine metabolism." Journal of Neural Transmission,Supplement. 41. 327-333 (1994)
[Publications] 直井信: "パーキンソン病の基礎と臨床;病因" 治療. 76. 1135-1142 (1994)
[Publications] 直井信: "神経化学研究の新たなる展望" 生物資料分析. 17. 38-40 (1994)
[Publications] 直井信: "パーキンソン病発症神経毒" 細胞工学. 12. 788-792 (1994)
[Publications] Msaruyama,W.: ""Alzheimer's and Parkinson's Diseases;Recent Development" Dopamine-derived isoquinolines as dopaminergic neurotoxins and oxidative stress" Plenum Press (印刷中), (1995)
[Publications] Naoi,M.: ""Alzheimer's and Parkinson's Diseases;Recent Development"Metabolic bioactivation of endogenous isoquinolines as dopaminergic neurotoxins to elicit Parkinson's Disease." Plenum Press (印刷中), (1995)
[Publications] Naoi,M.: ""Progress in Brain Research" Dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines;Oxidation and Neurotoxicity (印刷中)" Elsevier Science Publishers, (1995)
[Publications] Nagatsu,T.: ""Advances in Research on Neurodegeneration,Vol.2;Etiopathogenensis" Endogenous MPTP-like amines in the brain:Isoquinlines." Birkhauser, 11 (1994)
[Publications] Naoi,M.: ""Tyrosine hydroxylase;from Discovery to Cloning"Allosteric regulation of tyrosine hydroxylase activity by its co-factor tetrahydrobiopterin." VSP Press, 14 (1993)

1994 Fiscal Year Annual Research Report

イソキノリンによるパーキンソン病モデルの作成

Principal Investigator

直井 信 名古屋工業大学, 工学部, 教授 (50022786)

Research Products

[Publications] Maruyama,W.: "N-Methyl(R)salsolinol produced hydroxyl radicals;Involvement to neurotoxicty." Free Radical Biology & Medicine. (印刷中). (1995)

[Publications] Maruyama,W.: "Dopamine-derived 1-methyl-6,7-dihydroxyisoquinolines as hydroxyl radical promoters and scavengers in the rat brain:In vivo and in vitro studies." Journal of Neurochemisitry. (印刷中). (1995)

[Publications] Takahashi,T.: "Uptake of a neurotoxin-candidate,(R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system." Journal of Neural Transmission [GenSect]. 98. 107-118 (1994)

[Publications] Naoi,M.: "Inhibition of type A monoamine oxidase by 2(N)-methyl-6,7-dihydroxyisoquinoliniun ions." Neurochemistry International. 25. 991-995 (1994)

[Publications] 丸山和佳子: "Droxydopaのヒト体内における代謝の検討" 臨床神経学. 34. 991-995 (1994)

[Publications] 丸山和佳子: "Droxydopa(L-threo-3,4-dihyroxyphenylserine)のヒト脳内モノアミン代謝におよぼす影響" 臨床神経学. 34. 985-990 (1994)

[Publications] Matsubara,K.: "Structural studies of condensationproducts of biogenic amines as inhibitors of tryptophan hydroxylase." Brain Research. 655. 121-127 (1994)

[Publications] Naoi,M.: "Binding of 1,2(N)-dimethyl-6,7-digyfroxy-isoquinolinium ion to melanin;effects of ferrous and ferric ion on the binding." Neuroscience Letters. 171. 9-12 (1994)

[Publications] Naoi,M.: "Inhibition of tryptophan hyddroxylase by dopamine and the precursor amino acids." Biochemical Pharmacology. 48. 207-212 (1994)

[Publications] Maruyama,W.: "A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine,a precursor amino acid of norepinephrine,in the brain;Studies by in vivo microdialysis." Journal of Neural Transmission [P-D Sect]. 7. 21-33 (1994)

[Publications] Nakahara,D.: "Characterization of the in vivo action of (R)salsolinol,an endogenous metabolire by-product of alcohol,on serotonin and dopamine metabolism:A microdialysis study." Brain Research. 644. 226-233 (1994)

[Publications] Maruyama,W.: "Inhibition of tyrosine hydroxylase by a dopamine neurotoxin,1-methyl-4-phenylpyridini-um ion;depletion of allostery to the biopterin cofactor." Life Sciences. 55. 207-212 (1994)

[Publications] Kajita,M.: "Endogenous synthesis of N-methyl-norsalsolinol in rat brain during in vivo microdialysis with epinine." Journal of Chromatography B. 654. 263-269 (1994)

[Publications] Hattori,S.: "Striatal dopamine turnover during treadmill running in the rat:Relation to the speed of running." Brain Research Bulletin. 35. 41-49 (1994)

[Publications] 丸山和佳子: "脳内在性Catecholisoquinolinesによるパーキンソン病ラットモデルの作成" 神経化学. 53. 268-269 (1994)

[Publications] Naoi,M.: "Novel toxins and Parkinson's disease:N-methylation and oxidation as metabolic bioactivation as metabolic activation of neurotoxin" Journal of Neural Transmission,Suppliment. 41. 197-205 (1994)

[Publications] Maruyama,W.: "Food-derived heterocyclic amines,3-amino-1,4-dimethyl-5H-pyrid[4,3-b] indol and related amines,as inhibitiors of monoamine metabolism." Journal of Neural Transmission,Supplement. 41. 327-333 (1994)

[Publications] 直井信: "パーキンソン病の基礎と臨床;病因" 治療. 76. 1135-1142 (1994)

[Publications] 直井信: "神経化学研究の新たなる展望" 生物資料分析. 17. 38-40 (1994)

[Publications] 直井信: "パーキンソン病発症神経毒" 細胞工学. 12. 788-792 (1994)

[Publications] Msaruyama,W.: ""Alzheimer's and Parkinson's Diseases;Recent Development" Dopamine-derived isoquinolines as dopaminergic neurotoxins and oxidative stress" Plenum Press (印刷中), (1995)

[Publications] Naoi,M.: ""Alzheimer's and Parkinson's Diseases;Recent Development"Metabolic bioactivation of endogenous isoquinolines as dopaminergic neurotoxins to elicit Parkinson's Disease." Plenum Press (印刷中), (1995)

[Publications] Naoi,M.: ""Progress in Brain Research" Dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines;Oxidation and Neurotoxicity (印刷中)" Elsevier Science Publishers, (1995)

[Publications] Nagatsu,T.: ""Advances in Research on Neurodegeneration,Vol.2;Etiopathogenensis" Endogenous MPTP-like amines in the brain:Isoquinlines." Birkhauser, 11 (1994)

[Publications] Naoi,M.: ""Tyrosine hydroxylase;from Discovery to Cloning"Allosteric regulation of tyrosine hydroxylase activity by its co-factor tetrahydrobiopterin." VSP Press, 14 (1993)

直井信名古屋工業大学, 工学部, 教授 (50022786)