L-DOPA OVERLOAD: MECHANISMS FOR THE SIDE EFFECTS.

L多巴是多巴胺(DA)的前体，是治疗老年痴呆症状最有效的药物。 帕金森氏病(PD)，但其使用受到连续使用后发生的严重副作用的限制。这个 原因不明，但在L-多巴治疗期间，组织L-多巴大大超过了几乎检测不到的 因此，L-多巴的超负荷对儿茶酚胺系统起着不利的调节作用。我们的 假说认为，感知高水平的L-多巴和多巴胺作为底物的酶，如L- 芳香族氨基酸脱羧酶(LAAD)、多巴胺(DA)-β羟基酶(DBH)和儿茶酚-O- 甲基转移酶(COMT)以及催化合成的蛋氨酸腺苷转移酶(MAT) 在辅因子中，诱导了代谢L-多巴和多巴胺的S-腺苷蛋氨酸。的归纳 COMT和MAT会增加L-多巴和多巴胺的代谢，并会产生干扰甲基 代谢物。胸径的诱导会产生异位去甲肾上腺素(NE)，这可能稀释DH的作用。 黑质纹状体通路中的DA。诱导的LAAD将加速L-多巴对DA的催化作用，产生DA 涌动。DA反过来会导致LAAD的反馈抑制，产生脉动的DA供应，这可能有助于 造成了开关效应。我们的假设是基于初步结果表明L-多巴诱导了 COMT和MAT，这些酶反过来又代谢L-多巴和多巴胺。L-多巴还可诱导脑LAAD。这个 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， 分别降低和增加运动活性、DA受体结合和3-O-甲基多巴(3-O-甲基多巴)。 在注射L多巴的帕金森病大鼠模型和L多巴治疗的帕金森病患者中，均出现高水平的OMD)。3- 口服避孕药降低L-多巴的药效和多巴胺的周转。研究还发现，心律失常在 L多巴治疗的帕金森病患者是NE升高所致。具体目标是：(1)继续深造 L-多巴诱导的COMT、MAT以及LAAD和DBH。(#2)确定是否诱导 LAAD导致DA激增，且DA反过来计数器抑制LAAD，从而导致DA脉动供应 这可能与开关效应有关。(#3)将胸径诱导和NE生产本地化 黑质纹状体神经元，并确定纹状体组织中NE是否与DA共同释放。(#4)评估 3-O-甲基多巴、3-MT和DIMPEA的行为和受体效应 L-多巴的副作用。研究的重点将是基底节的变化。生物化学 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试剂 当L-多巴的有益效果不会妥协的时候。

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.