靶向犬尿氨酸途径在神经退行性疾病中的治疗潜力。

Therapeutic potential of targeting kynurenine pathway in neurodegenerative diseases.

作者信息

Shen Hualiang, Xu Xinde, Bai Yalong, Wang Xiaoping, Wu Yibin, Zhong Jia, Wu Qiyi, Luo Yanjuan, Shang Tianbo, Shen Runpu, Xi Meiyang, Sun Haopeng

机构信息

Zhejiang Engineering Research Center of Fat-soluble Vitamin, Shaoxing University, Shaoxing, 312000, China; College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China.

Zhejiang Medicine Co. Ltd., Shaoxing, 312500, China.

出版信息

Eur J Med Chem. 2023 May 5;251:115258. doi: 10.1016/j.ejmech.2023.115258. Epub 2023 Mar 8.

DOI:10.1016/j.ejmech.2023.115258

PMID:36917881

Abstract

Kynurenine pathway (KP), the primary pathway of L-tryptophan (Trp) metabolism in mammals, contains several neuroactive metabolites such as kynurenic acid (KA) and quinolinic acid (QA). Its imbalance involved in aging and neurodegenerative diseases (NDs) has attracted much interest in therapeutically targeting KP enzymes and KP metabolite-associated receptors, especially kynurenine monooxygenase (KMO). Currently, many agents have been discovered with significant improvement in animal models but only one aryl hydrocarbon receptor (AHR) agonist 30 (laquinimod) has entered clinical trials for treating Huntington's disease (HD). In this review, we describe neuroactive KP metabolites, discuss the dysregulation of KP in aging and NDs and summarize the development of KP regulators in preclinical and clinical studies, offering an outlook of targeting KP for NDs treatment in future.

摘要

犬尿氨酸途径（KP）是哺乳动物中L-色氨酸（Trp）代谢的主要途径，包含几种神经活性代谢产物，如犬尿喹啉酸（KA）和喹啉酸（QA）。其在衰老和神经退行性疾病（NDs）中的失衡已引起人们对以KP酶和与KP代谢产物相关的受体（尤其是犬尿氨酸单加氧酶（KMO））为治疗靶点的极大兴趣。目前，已发现许多药物在动物模型中具有显著改善，但只有一种芳烃受体（AHR）激动剂30（拉喹莫德）已进入治疗亨廷顿舞蹈病（HD）的临床试验。在本综述中，我们描述了神经活性KP代谢产物，讨论了衰老和NDs中KP的失调，并总结了临床前和临床研究中KP调节剂的进展，展望了未来针对NDs治疗靶向KP的前景。