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c-Jun氨基末端激酶抑制剂作为阿尔茨海默病新疗法的潜在先导药物

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer's Diseases.

作者信息

Hepp Rehfeldt Stephanie Cristine, Majolo Fernanda, Goettert Márcia Inês, Laufer Stefan

机构信息

Graduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado CEP 95914-014, Rio Grande do Sul, Brazil.

Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre CEP 90619-900, Rio Grande do Sul, Brazil.

出版信息

Int J Mol Sci. 2020 Dec 18;21(24):9677. doi: 10.3390/ijms21249677.

DOI:10.3390/ijms21249677
PMID:33352989
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7765872/
Abstract

Alzheimer's Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.

摘要

随着人口寿命的延长，阿尔茨海默病（AD）正变得越来越普遍。对于60岁以上的个体，全球AD的患病率估计为40.19%。关于该疾病引起的认知衰退，丝裂原活化蛋白激酶（MAPK）途径，如c-Jun氨基末端激酶（JNK）途径，参与神经元和突触的渐进性丧失、脑萎缩以及脑室增大，这些过程由突触功能障碍、氧化应激和兴奋性毒性激活。如今，AD症状是可控的，但疾病本身仍然无法治愈，因此，鉴于JNK以参与传播促凋亡信号而闻名，对JNK3的抑制已被探索为一种可能的治疗靶点。本综述旨在介绍JNK的生物学方面，重点关注JNK3及其与AD的关系。由于III期临床试验中的几种药物/化合物失败，还探讨了可用于AD治疗的抑制剂的最新进展。在本综述中，将描述和讨论MAPK家族的一般方面、治疗靶点以及模型中的实验性治疗。

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