| Project/Area Number |
06557143
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE,YOKOHAMA 236, JAPAN. |
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Principal Investigator |
MISU Yoshimi YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE,PHARMACOLOGY PROFESSOR, 医学部, 教授 (10025687)
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| Co-Investigator(Kenkyū-buntansha) |
KOJIMA Atsuyuki SUMITOMO PHARMACEUTICAL CO., DRUG DEVELOPMENT II CHIEF LEADER, 創薬第2研, 主席
FUJI Kaoru KYOTO UNIVERSITY,INSTITUTE OF CHEMISTRY PROFESSOR, 化学研究所, 教授 (20027056)
MIYAMAE Takeaki YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE,PHARMACOLOGY RESEACH ASSOCIATE, 医学部, 助手 (00239435)
GOSHIMA Yoshio YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE,PHARMACOLOGY ASSISTANT PROFESSOR, 医学部, 講師 (00153750)
UEDA Hiroshi YOKOHAMA CITY UNIVERSITY SCHOOL OF MEDICINE,PHARMACOLOGY ASSOCIATE PROFESSOR, 医学部, 助教授 (00145674)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 1995: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1994: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | DOPA / Parkinson's model rat striata / Microdialysis / Basal glutamate release / Basal DOPA release / Microinjection into NTS / Competitive DOPA antagonist / Agonist for "DOPAergic receptors" / 弧束核微量注入 / L-ドーパ / L-ドーパメチルエステル / L-ドーパメチルエステル誘導体 / 線条体微量透析 / 内因性アセチルコリン遊離 / パーキンソン病モデル / アフリカツメガエル卵母細胞 / 内因性ドーパ自発性遊離 |
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| Research Abstract |
Effects of L-DOPA on gultamate release during striatal microdialysis of i.v.t.6-OHDA-treated conscious rats. In control rats, L-DOPA 10-100 nM locally perfused in striata via probes concentration-dependently increased glutamate release, 100 nM-induced increase by 136% was completely Ca^2+-dependent and TTX-sensitive, while D-DOPA or dopaminwe 100 mM produced no effect. The noneffective 10 nM in control rats increased gultamate release by 187% in i.v.t.6-OHDA-treated rats. Supersensitization of striatal gultamate release to L-DOPA was evident.
Screening for a stable competitive L-DOPA antagonist. Newly synthesized DOPA methyl amide was stable on basal DOPA release during striatal microdialysis of conscious rats, but produced no antagonism against postsynaptic depressor and bradycardic responses to DOPA Microinjced into depressor sites of the nucleus tractus solitarii (NTS) of anesthetized rats, while DOPA cyclo propyl methyl ester antagonized the responses to DOPA in NTS,but was easily c
… More
onverted to DOPA during microdialysis. No merit was seen compared to DOPA methy ester. Newly synthesized tentatively named "Compound M" 1 mug microinjected into NTS completely antagonized the responses to DOPA 60 ng and the degree of conversion to DOPA During microdialysis was clearly less than that of DOPA methyl ester. This seems to be a suitable mother compound to explore a stable competitive antogonist for DOPA in further studies.
Screening for a DOPA agonist. L-threo-3,4-Dihydroxyphenylserine (L-threo-DOPS) is though to be an artificial precursor for noradrenaline by DOPA decarboxylase. However, L-threo-DOPS stereoselectively facilitated increase in noradrenaline release via presynaptic beta-adrenoceptors from hypothalamic slices and it microinjected into NTS produced postsynaptic depressor and bradycardic responses. These two types of responses were seen under inhibition of DOPA decarboxylase and were antagonized by DOPA methyl ester in a competitive manner. L-threo-DOPA is an agonist for "L-DOPAergic receptors". Less
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