...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Current drug targets. CNS and neurological disorders >3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease.
【24h】

3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease.

机译：3，4-二羟基苯基乙醛：帕金森氏病的神经保护疗法的潜在目标。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

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 (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.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.
机译：对于帕金森氏病（PD）中黑质（SN）多巴胺（DA）神经元选择性丢失的最简单解释是，DA或代谢物具有神经毒性。最近，一系列研究表明，DA的MAO代谢产物3,4-二羟基苯基乙醛（DOPAL）是触发PD中DA神经元丢失的关键内源性毒素：1.遗传性PD包含α-突触核蛋白基因（α -syn）。研究表明，DA代谢产物是α-syn神经毒性的介质，而DOPAL的毒性是体内DA的1000倍。 2.在PD SN中发现线粒体复合体I缺乏。在体外和体内，对复合物I的抑制都会导致DOPAL水平升高和DA神经元死亡。 3. L-DOPA是用于治疗PD的DA的前体，具有毒性，并有助于PD的发展。经L-DOPA处理的大鼠纹状体DOPAL增加了18倍。 4.游离羟基（.OH）触发α-syn聚集为其毒性形式。具有H（2）O（2）的DOPAL生成OH自由基。这些研究为限制DOPAL毒性和PD的发展提供了几种治疗策略：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，从而限制了L-DOPA形成的DOPAL的量。 DOPA。 2.与MAO-B抑制剂相比，非特异性MAO抑制剂可能更有效地降低DA中DOPAL的产生。 3.新型更有效和更有针对性的自由基清除剂可以阻断DOPAL毒性。 4.辅酶Q（10）增加了复合物I的活性和尼古丁腺嘌呤二核苷酸（NAD）的合成，因此可以通过使用NAD作为辅因子的醛脱氢酶增强DOPAL分解代谢。 5. DA吸收阻滞剂可用于限制神经内DOPAL的产生。 6.牛磺去氧胆酸是一种凋亡抑制剂，在亨廷顿舞蹈症模型中显示出有效的作用，也可能被证明可以有效阻断PD的DOPAL毒性。 7.阻断α-syn聚集的药物应限制DOPAL毒性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号