1994 Fiscal Year Final Research Report Summary
A possible new drug for Parkinson's disease regulating dopamine receptor genes.
| Project/Area Number |
04557037
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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 |
Neurology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KANAZAWA Ichiro Faculty of Medicine, The University of Tokyo, Professor, 医学部(病), 教授 (30110498)
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| Co-Investigator(Kenkyū-buntansha) |
KUSUNOKI Susumu The University of Tokyo Faculty of Medicine, assistant professor, 医学部, 助手 (90195438)
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| Project Period (FY) |
1992 – 1994
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| Keywords | lovodopa / dopamine receptor / promotor analysis / BDNF / POV family / cytochrome P-450 / Parkinson's disease |
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| Research Abstract |
The aims of the present study are to investigate the pharmacodynamics of levodopa, to elucidate the relationship between levodopa and neurotrophic factors, to analyze the gene for dopamine receptors and to clarify the genetic background of idiopathic Parkinson's disease. Summary of the results are as follows :
(1) In the long-term treatment of Parkinson's disease with levodopa, we often encountered with a loss of efficacy. In the study for elucidating the mechanism of this phenomenon, we found that the long-term oral administration of levodopa brought about an acceleration of absorption of levodopa from gut.
(2) In order to investigate the relationship between levodopa and the neurotrophic factors, we investigated the effect of orally administered levodopa on the amopunt of expressed mRNA level of brain-derived neurotrophic factos (BDNF) in the striatum of rat. mRNA for BDNF significantly increased from 2 hour through 16 hours after the administration of the final dose of levodopa. Interestingly, this increase was abolished by the co-administration of haloperidol.
(3) The gene for the human D1 dopamine receptor was cloned and investigated the expression dynamics in terms of the regulation mechanisms. Collaborated with Dr. Mouradian in NIH,we found that the Brn-4, a member of the POU family, bound to the D1 enhancer at 2 sites and suppressed the D1 gene expression.
(4) Sporadic Parkinson's disease could be caused by a toxic material coming from outside, and this material could be normally detoxicated and poorly metabolised in Parkinson's disease patient. We investigated the relationship between the detoxicating activity and the genetic polymorphism of cytochrome p-450 and found a positive relationship between them.
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