Insight into JNK Inhibition-based Strategy for the Treatment of Alzheimer's Disease

Q4 Pharmacology, Toxicology and Pharmaceutics

Current Enzyme Inhibition Pub Date : 2023-08-16 DOI:10.2174/1573408019666230816143357

G. Zyuz’kov, L. Miroshnichenko, T. Polyakova, E. Simanina, Alexander Vasil `evich Chayikovskyi, Larisa Yur`evna Kotlovskaya

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Abstract

Existing drugs for the treatment of Alzheimer's disease do not meet the basic requirements. Therefore, it is necessary to search for fundamentally new targets for the discovery of drugs for Alzheimer's disease (AD). When creating approaches to stimulate neurogenesis, such a search is promising to conduct as part of the development of a strategy for targeted regulation of intracellular signal transduction in regeneration-competent cells (RCCs). Moreover, the participation of c-Jun N-terminal kinases (JNK) in the regulation of the functions of the nervous tissue and neuroglial cells is known. The aim of the work was to study the effect of the JNK inhibitor (IQ-1S) on exploratory behavior and cognitive functions in aged mice (16-month-old male C57BL/6 mice as a model of AD) in combination with the dynamics of shifts in the RCCs functioning (nervous tissue progenitors: neural stem cells (NSCs) and neuronal-committed progenitors (NCPs); neuroglial cells: astrocytes, oligodendrocytes, microglial cells). The studies were carried out on male C57BL/6 mice aged 16 months as model of Alzheimer's disease. We studied the effect of the JNK inhibitor on exploratory behavior, conditioned reflex activity, and on the functioning of RCCs in the subventricular zone of the cerebral hemispheres (SVZ). NCPs and neuroglial cells of different types were obtained by immunomagnetic separation. We observed significant changes in exploratory behavior and impaired conditioned reflex activity in aged C57BL/6 mice. The administration of the JNK inhibitor led to a significant correction of age-related behavioral and memory disorders in aged mice. At the same time, against the background of JNK inhibition-based therapy, an increase in mitotic activity and the content of both NSCs and NCPs in the SVZ was noted. However, these shifts were more pronounced in committed precursors. The phenomenon of the inhibition of NSC specialization under the influence of a pharmacological agent was also revealed. In addition, the JNK inhibitor caused an increase in the secretion of neurotrophic growth factors by oligodendrocytes and microglial cells. The findings open up prospects for the development of JNK targeting-based approaches for the treatment of AD.

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基于JNK抑制的阿尔茨海默病治疗策略

现有的治疗阿尔茨海默病的药物不符合基本要求。因此，有必要从根本上寻找阿尔茨海默病(AD)药物的新靶点。在创造刺激神经发生的方法时，这样的研究有望作为再生能力细胞(RCCs)中细胞内信号转导靶向调节策略发展的一部分。此外，已知c-Jun n -末端激酶(JNK)参与神经组织和神经胶质细胞功能的调节。本研究的目的是研究JNK抑制剂(eq - 1s)对老年小鼠(16月龄雄性C57BL/6小鼠作为AD模型)探索性行为和认知功能的影响，并结合rcc功能(神经组织祖细胞:神经干细胞(NSCs)和神经元承诺祖细胞(ncp);神经胶质细胞:星形胶质细胞、少突胶质细胞、小胶质细胞)。本研究以16月龄雄性C57BL/6小鼠作为阿尔茨海默病模型。我们研究了JNK抑制剂对探索行为、条件反射活动和大脑半球室下区rcc功能的影响。免疫磁分离获得不同类型的ncp和神经胶质细胞。我们观察到老年C57BL/6小鼠的探索行为和条件反射活动的显著变化。JNK抑制剂的施用导致老年小鼠年龄相关的行为和记忆障碍的显著纠正。同时，在以JNK抑制为基础的治疗背景下，注意到SVZ中有丝分裂活性和NSCs和ncp含量的增加。然而，这些变化在有前科的前体中更为明显。还发现了在药物作用下抑制NSC特化的现象。此外，JNK抑制剂引起少突胶质细胞和小胶质细胞分泌神经营养生长因子的增加。这一发现为基于JNK靶向治疗阿尔茨海默病的方法的发展开辟了前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

1.30

自引率

0.00%

发文量

期刊介绍： Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.