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新型NADPH氧化酶-2抑制剂作为潜在的抗炎和神经保护剂

Novel NADPH Oxidase-2 Inhibitors as Potential Anti-Inflammatory and Neuroprotective Agents.

作者信息

Juric Matea, Rawat Varun, Amaradhi Radhika, Zielonka Jacek, Ganesh Thota

机构信息

Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.

出版信息

Antioxidants (Basel). 2023 Aug 23;12(9):1660. doi: 10.3390/antiox12091660.

DOI:10.3390/antiox12091660
PMID:37759963
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10525516/
Abstract

A family of seven NADPH oxidase enzymes (Nox1-5, Duox1-2) has been implicated in a variety of diseases, including inflammatory lung diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Here, we report the results of our studies aimed at developing novel brain-permeable Nox2 inhibitors with potential application as neuroprotective agents. Using cell-based assays, we identified a novel Nox2 inhibitor, TG15-132, that prevents PMA-stimulated oxygen consumption and reactive oxygen species (superoxide radical anion and hydrogen peroxide) formation upon acute treatment in differentiated HL60 cells. Long-term treatment with TG15-132 attenuates the induction of genes encoding Nox2 subunits, several inflammatory cytokines, and iNOS in differentiated THP-1 cells. Moreover, TG15-132 shows a relatively long plasma half-life (5.6 h) and excellent brain permeability, with a brain-to-plasma ratio (>5-fold) in rodent models. Additionally, TG15-132 does not cause any toxic effects on vital organs or blood biomarkers of toxicity in mice upon chronic dosing for seven days. We propose that TG15-132 may be used as a Nox2 inhibitor and a potential neuroprotective agent, with possible further structural modifications to increase its potency.

摘要

一个由七种NADPH氧化酶（Nox1 - 5，Duox1 - 2）组成的家族与多种疾病有关，包括炎症性肺病、神经退行性疾病、心血管疾病和癌症。在此，我们报告了旨在开发新型可透过血脑屏障的Nox2抑制剂并将其作为神经保护剂进行潜在应用的研究结果。通过基于细胞的检测，我们鉴定出一种新型Nox2抑制剂TG15 - 132，在分化的HL60细胞中急性处理时，它可阻止佛波酯（PMA）刺激的氧气消耗和活性氧（超氧阴离子自由基和过氧化氢）形成。在分化的THP - 1细胞中，用TG15 - 132长期处理可减弱编码Nox2亚基、几种炎性细胞因子和诱导型一氧化氮合酶（iNOS）的基因的诱导。此外，TG15 - 132显示出相对较长的血浆半衰期（5.6小时）和出色的血脑通透性，在啮齿动物模型中的脑血比（>5倍）。另外，在小鼠中连续给药七天后，TG15 - 132对重要器官或毒性血液生物标志物未产生任何毒性作用。我们提出TG15 - 132可用作Nox2抑制剂和潜在的神经保护剂，可能需要进一步进行结构修饰以提高其效力。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a393/10525516/432ac93eb964/antioxidants-12-01660-sch001.jpg
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