L-DOPA OVERLOAD: MECHANISMS FOR THE SIDE EFFECTS.

左旋多巴超载：副作用的机制。

• 批准号: 7047532
• 负责人: CLIVEL G. CHARLTON
• 金额: $ 20.37万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-03 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047532
• 关键词: Parkinson' s disease; S adenosylmethionine; aromatic L aminoacid decarboxylase; behavior test; catechol methyltransferase; corpus striatum; dopamine; dopamine beta monooxygenase; dopamine receptor; drug adverse effect; enzyme activity; enzyme induction /repression; high performance liquid chromatography; immunocytochemistry; laboratory mouse; levodopa; methionine adenosyltransferase; methylphenyltetrahydropyridine; neuropharmacology; neurotransmitter transport; norepinephrine; pharmacokinetics; protein localization; protein structure function; psychomotor function; substantia nigra

DESCRIPTION (provided by applicant):  L-dopa, the precursor of dopamine (DA), is the most effective drug used for treating the symptoms of Parkinson's disease (PD), but its use is limited by serious side effects that occur after continuous use. The causes are unknown, but during L-dopa treatments tissue L-dopa greatly exceeds the barely detectable levels that normally exist, therefore the overload of L-dopa dys-regulates the catecholamine system. Our hypothesis proposes that enzymes that sense the high levels of L-dopa and DA as substrates, such as L- aromatic amino acid decarboxylase (LAAD), dopamine (DA)-beta hydroxylase (DBH) and catechol-O- methyltransferase (COMT), as well as methionine adenosyltransferase (MAT) that catalyses the synthesis of the cofactor, S-adenosylmethionine, for the metabolism of L-dopa and DA, are induced. The induction of COMT and MAT will increase the metabolism of L-dopa and DA and will generate interfering methyl metabolites. The induction of DBH will produce ectopic norepinephrine (NE) that may dilute the efficacy of DA in the nigrostriatal pathway. The induced LAAD will accelerate the catalysis of L-dopa to DA, causing DA surge. DA in turn will cause feedback inhibition of LAAD, generating a pulsatile supply of DA that may help to cause the on-off effects. "We base our hypothesis on preliminary results showing that L-dopa induced COMT and MAT, enzymes that, in turn, metabolize L-dopa and DA. L-dopa also induced brain LAAD. The methyl metabolites of DA, 3-methoxytyramine (3-MT) and 3,4-dimethoxyl-phenylethylamine (DIMPEA), respectively, decreased and increased motor activities and DA receptor binding and 3-O-methyldopa (3- OMD) occurred in high levels in rat models of PD injected with L-dopa and in L-dopa-treated PD patients. 3- OMD decreased the efficacy of L-dopa and the turnover of DA. Studies also found that cardiac arrhythmia in L-dopa-treated PD patients was caused by increased NE.  The specific aims are: (# 1) To further study the induction of COMT, MAT as well as LAAD and DBH by L-dopa. (# 2) Determine if the induction of LAAD causes DA surges and that DA in turn counter inhibits LAAD causing a pulsatile supply of DA that may be related to the on-off effects. (# 3) Localize DBH induction and NE production in nigrostriatal neurons and determine if NE is co-released with DA from striatal tissues. (#4) Evaluate the behavioral and receptor effects of 3-O-methyldopa, 3-MT and DIMPEA, to know if they contribute to the side effects of L-dopa. "The studies will focus on changes in the basal ganglia. The biochemical pathways being studied are at the crux of drug actions and the results can be readily translated into therapy, so, the outlook for the project is to find agents that will target specific enzymes and metabolic pathways at times when the beneficial effects of L-dopa will not be compromised.

描述（由申请人提供）：多巴胺（DA）的前体L-DOPA是用于治疗帕金森氏病（PD）症状的最有效药物，但其使用受到持续使用后发生的严重副作用的限制。原因是未知的，但是在L-DOPA处理期间，组织L-DOPA大大超过了通常存在的几乎无法检测的水平，因此L-DOPA DYS的过载可以调节儿茶酚胺系统。我们的假设提出，将高水平的L-DOPA和DA视为底物，例如L-芳族氨基酸脱羧酶（LAAD），多巴胺（DA）-Beta羟化酶（DBH）（DBH）和Catechol-O-O-O-甲基转移酶（COMT），以及甲基化甲基甲烯基甲基化酶（MAT）catase catase catase catase catase catase catase catase catase catase catase catase catase cate（cate），诱导辅助因素，用于L-DOPA和DA的代谢的s-腺苷甲硫代。 COMT和MAT的诱导将增加L-DOPA和DA的代谢，并会产生干扰甲基代谢物。 DBH的诱导将产生异位去甲肾上腺素（NE），该肾上腺素（NE）可能会稀释DA在黑质纹状体途径中的疗效。诱导的LAAD将加速L-DOPA的催化为DA，从而导致DA激增。 DA反过来会导致对LAAD的反馈抑制，从而产生DA的脉动供应，这可能有助于引起关闭效应。 “我们基于初步结果的假设，表明L-DOPA诱导了COMT和MAT，酶，这些酶反过来代谢L-DOPA和Da。L-DOPA也诱导了脑LAAD。DA，3-甲氧基胺（3--MT）和3,4-二甲氧基 - 二甲基甲基甲基甲基甲基甲基甲基甲基甲基胺的甲基代谢产物（3-甲氧基型）的甲基化代谢物（在注射L-DOPA的PD和L-DOPA处理的PD患者中，在高水平的PD中，结合和3-O的甲基菌（3- OMD）都会发生。 l-dopa（＃2）的COMT，MAT和DBH。 （＃4）评估3-O-甲基，3-MT和DIMPEA的行为和受体效应，以了解它们是否有助于L-DOPA的副作用。 “研究将集中于基础神经节的变化。正在研究的生化途径是毒品作用的关键，结果很容易将其转化为治疗，因此，该项目的前景是在L-DOPA对L-DOPA的有益效应的情况下，有时会找到针对特定酶和代谢途径的试剂。