Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism
Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism
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DOI：
10.3390/molecules25030564
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发表时间：
2020-01
期刊：
影响因子：
4.6
通讯作者：
Masaru Tanaka;Zsuzsanna Bohár;L. Vécsei
中科院分区：
文献类型：
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作者：
Masaru Tanaka;Zsuzsanna Bohár;L. Vécsei
全世界有5000万人患有痴呆症，这是一组影响认知和社会功能的症状，病情发展严重到足以干扰日常生活。阿尔茨海默病（AD）占痴呆病例的大部分。病理和临床发现导致了对AD发病机制的几种假设，发现了正反馈回路的存在，另外观察到色氨酸代谢分支犬尿氨酸（KYN）途径的紊乱。无论是痴呆的原因还是结果，观察到神经毒性KYN代谢物水平升高，可能上调AD发病机制的多个反馈回路。美金刚是一种n -甲基- d -天冬氨酸谷氨酸受体（NMDAR）拮抗剂，属于仅有的两类获准临床使用的药物之一，但其他NMDAR调节剂迄今为止尚未探索。内源性KYN通路代谢物kynurenic acid （KYNA）同样抑制兴奋毒性NMDAR。除了抗兴奋毒性外，KYNA是一种多靶点化合物，可触发抗炎和抗氧化活性。修改KYNA水平是一种潜在的多靶点策略，可以使紊乱的KYN通路正常化，从而减轻并列的AD发病机制。在这篇综述中，提出并讨论了通过改变KYNA水平来维持KYN代谢，以寻找一种新的抗痴呆进展的先导化合物。
Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.