L-DOPA OVERLOAD: MECHANISMS FOR THE SIDE EFFECTS.

左旋多巴超载：副作用的机制。

• 批准号: 7777250
• 负责人: CLIVEL G. CHARLTON
• 金额: $ 33.36万
• 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/7777250
• 关键词: 3-methoxytyramine; 3-methoxytyrosine; Adverse effects; Affinity; Animals; Aromatic-L-Amino-Acid Decarboxylases; Arrhythmia; Basal Ganglia; Behavioral; Biochemical Pathway; Brain; Catalysis; Catechol O-Methyltransferase; Catecholamines; Catechols; Chronic; Clinical; Clinical Trials; Corpus striatum structure; Development; Disease model; Doctor of Philosophy; Dopa; Dopamine; Dopamine Receptor; Dopamine-beta-monooxygenase; Drug effect disorder; Drug usage; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Equilibrium; Feedback; Genes; Goals; Investigation; Kinetics; Levodopa; Ligands; Measures; Metabolic Pathway; Metabolism; Methionine; Modeling; Motor Activity; Neurons; Neurotransmitters; Norepinephrine; Outcome; Outcomes Research; Parents; Parkinson Disease; Pathway interactions; Patients; Phenethylamines; Production; Proteins; Radioactive; Rattus; Receptor Activation; Regulation; Research Personnel; Role; Stress; Symptoms; System; Testing; Time; Tissues; Toxic effect; Transferase; Translating; base; bench to bedside; cofactor; dopaminergic neuron; enzyme activity; methionine adenosyltransferase; nigrostriatal pathway; novel; programs; receptor; receptor binding; response

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.

左旋多巴是多巴胺 (DA) 的前体，是治疗以下症状最有效的药物 帕金森病（PD），但其使用受到连续使用后出现严重副作用的限制。 原因尚不清楚，但在左旋多巴治疗期间，组织左旋多巴大大超过了几乎检测不到的水平 正常存在的水平，因此左旋多巴的超负荷会失调儿茶酚胺系统。 假设提出，感应高水平 L-多巴和 DA 作为底物的酶，例如 L- 芳香族氨基酸脱羧酶 (LAAD)、多巴胺 (DA)-β 羟化酶 (DBH) 和儿茶酚-O- 甲基转移酶 (COMT) 以及催化合成的甲硫氨酸腺苷转移酶 (MAT) 诱导 L-多巴和 DA 代谢的辅助因子 S-腺苷甲硫氨酸的活性。 COMT和MAT会增加左旋多巴和DA的代谢，并会产生干扰甲基 DBH 的诱导会产生异位去甲肾上腺素 (NE)，可能会削弱药物的功效。 黑质纹状体途径中的DA，诱导的LAAD会加速L-多巴对DA的催化，引起DA。 DA 反过来会引起 LAAD 的反馈抑制，产生 DA 的脉动供应，这可能有助于 ¿引起开关效应。我们的假设基于初步结果，表明左旋多巴诱导 COMT 和 MAT 这两种酶依次代谢左旋多巴和左旋多巴，也会诱导大脑 LAAD。 DA、3-甲氧基酪胺 (3-MT) 和 3,4-二甲氧基苯乙胺 (DIMPEA) 的甲基代谢物， 分别减少和增加运动活动和 DA 受体结合以及 3-O-甲基多巴 (3- OMD) 在注射左旋多巴的 PD 大鼠模型和接受左旋多巴治疗的 PD 患者中出现高水平 3-。 OMD 降低了左旋多巴的功效和 DA 的周转率 研究还发现心律失常。 左旋多巴治疗的PD患者是由于NE增加引起的。具体目标是： (# 1) 进一步学习 L-多巴诱导 COMT、MAT 以及 LAAD 和 DBH (# 2) 确定是否诱导。 LAAD 会导致 DA 浪涌，而 DA 反过来会抑制 LAAD，从而导致 DA 的脉动供应 (# 3) 将 DBH 诱导和 NE 生产本地化 (#4) 评估 3-O-甲基多巴、3-MT 和 DIMPEA 的行为和受体效应，了解它们是否有贡献 左旋多巴的副作用。研究将重点关注基底神经节的生物化学变化。 正在研究的途径是药物作用的关键，结果可以很容易地转化为治疗， 因此，该项目的前景是找到针对特定酶和代谢途径的药物 左旋多巴的有益作用不会受到损害的时期。