MAO-B致病机理及其天然抑制剂防治帕金森病研究进展

Pathogenic Mechanism of Monoamine Oxidase-B and Research Progress of its Natural Inhibitors for Treating Parkinson’s Disease

关键词:  帕金森病  单胺氧化酶B  生物碱  黄酮  香豆素

Key words:  Parkinson’s disease  monoamine oxidase-B  alkaloids  fllavones  coumarins

摘要:

多巴胺作为神经递质调控大脑的运动功能，而单胺氧化酶-B (monoamine oxidase-B, MAO-B)是催化多巴胺降解的关键代谢酶，且在MAO-B氧化脱氨的过程中，会产生H2O2等活性氧分子，其代谢产生大量强氧化性的自由基。在这一过程中，多巴胺水平下降和自由基诱发的氧化应激被公认为帕金森病（Parkinson’s disease, PD）的重要发病机制，故MAO-B为PD的关键治疗靶点，抑制MAO-B酶活力则代表了PD防治的有力手段。MAO-B抑制剂可“双管齐下”，多环节多途径对抗PD：一方面，减少多巴胺的降解，增加多巴胺在神经元突触间隙内的含量，进而改善早期帕金森样运动障碍。另一方面，清除自由基，减少氧化应激，保护多巴胺能神经元，延缓PD疾病进程。本综述从分子结构，对源于中药等天然药用植物的高活性MAO-B抑制剂的构效关系、抑制效价、抑制模式及作用位点等进行分类和总结。本研究首次基于MAO-B抑制角度，尝试为目前防治PD的单味中药或方剂挖掘活性物质基础，并为后续研发更高效低毒的新型MAO-B抑制剂提供参考。

Abstract:

Dopamine represents an important catecholamine neurotransmitter that controls movement, and monoamine oxidase-B (MAO-B) is the key enzyme responsible for dopamine metabolism. Meanwhile, active oxygen molecules such as H2O2 are generated in the process of MAO-B oxidation and deamination, and the metabolism of H2O2 results in a large number of strongly oxidizing free radicals. Dopamine deficiency and neurotoxicity triggered by free radicals are closely involved in the pathogenesis of Parkinson's disease (PD), therefore, MAO-B is generally considered as a key target for PD and inhibition of MAO-B enzymatic activity has been proved to be a powerful means for treating PD. In light of this, two pronged approach for prevention and therapy of PD by MAO-B inhibitors has emerged, on one hand, inhibition of MAO-B enzymatic activity is able to reduce dopamine degradation, further increase the amount of dopamine in the synaptic cleft of neurons, and finally ameliorate Parkinsonian motor defects. On the other hand, MAO-B inhibition could scavenge free radicals, reduce oxidative stress, and protect dopaminergic neurons, thus delay the disease progression of PD. In this review, we summarize the structure-activity relationships, inhibitory potency, inhibition modes and binding sites of highly active MAO-B inhibitors derived from natural medicinal plants including Chinese medicine. From the perspective of MAO-B inhibition, this paper attempts to explore, for the first time, the material basis of currently used single herbs and herbal formulas for preventing and treating PD, and provide a reference for the subsequent development of new MAO-B inhibitors with higher efficiency and lower toxicity.