3,4-Dihydroxyphenylacetaldehyde: A Potential Target for Neuroprotective Therapy in Parkinson's Disease
3,4-Dihydroxyphenylacetaldehyde: A Potential Target for Neuroprotective Therapy in Parkinson's Disease
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DOI：
10.2174/1568007033482913
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Burke, W. J.
中科院分区：
文献类型：
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作者：
Burke, W. J.
对于帕金森病 (PD) 中黑质 (SN) 多巴胺 (DA) 神经元选择性丧失的最简单解释是，DA 或其代谢物具有神经毒性。最近，一系列研究表明 DA 的 MAO 代谢物 3,4-二羟基苯乙醛 (DOPAL) 是引发 PD 中 DA 神经元损失的关键内源性毒素： 1. 遗传性 PD 含有 α-突触核蛋白 (alpha-syn) 基因突变。研究表明 DA 代谢物是 α-syn 神经毒性的介质，DOPAL 在体内的毒性比 DA 高 1000 倍。 2. PD SN 中发现线粒体复合物 I 缺陷。抑制复合物 I 会导致体外和体内 DOPAL 水平增加以及 DA 神经元死亡。 3. L-DOPA是DA的前体，用于治疗PD，具有毒性并会促进PD的进展。 L-DOPA 治疗的大鼠纹状体 DOPAL 增加了 18 倍。 4. 自由基（中心点 OH）引发 α-syn 聚集成有毒形式。 DOPAL 与 H2O2 生成中心点 OH 自由基。这些研究提供了几种限制 DOPAL 毒性和 PD 进展的治疗策略： 1. 通过早期使用 DA 受体激动剂（也可能是自由基清除剂）来延迟 L-DOPA 治疗的开始，限制 L-DOPA 形成的 DOPAL 量。 2. 非特异性 MAO 抑制剂可能比 MAO-B 抑制剂更有效地减少 DA 产生 DOPAL。 3. 更新、更有效、更有针对性的自由基清除剂可以阻止 DOPAL 毒性。 4. 辅酶 Q(10) 增加复合物 I 活性和烟碱腺嘌呤二核苷酸 (NAD) 合成，从而可以增强醛脱氢酶（使用 NAD 作为辅因子）的 DOPAL 分解代谢。 5. DA摄取阻滞剂可用于限制神经元内DOPAL的产生。 6. 牛磺熊去氧胆酸是一种细胞凋亡抑制剂，在亨廷顿病模型中被证明有效，也可能被证明能有效阻断 PD 中的 DOPAL 毒性。 7.阻断α-syn聚集的药物应限制DOPAL毒性。
The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (center dot OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H2O2 generates center dot OH radicals.These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.