吖啶苯并咪唑衍生物诱导保护性小胶质细胞极化和硅TDP-43相互作用─对肌萎缩侧索硬化症的潜在影响。

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-03-19 Epub Date: 2025-03-03 DOI:10.1021/acschemneuro.4c00791
Neeraja Revi, Muneshwar Nandeshwar, Dinesh Harijan, Sri Amruthaa Sankaranarayanan, Meet Joshi, Ganesan Prabusankar, Aravind Kumar Rengan
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引用次数: 0

摘要

异常的蛋白质聚集和相关的神经胶质细胞毒性导致大量的神经退行性疾病。大多数早期研究了解神经退行性疾病的进展和治疗集中在神经元损伤和修复潜力。随着越来越多的证据表明小胶质细胞和星形胶质细胞等胶质细胞在介导这些疾病中的作用,越来越多的研究致力于了解胶质细胞介导的炎症反应的作用以及它们如何导致神经炎症。肌萎缩性侧索硬化症(ALS)是一种迟发性神经退行性疾病,由TDP-43聚集影响运动神经元引起。促炎小胶质细胞被认为加重了疾病状况。在本研究中,研究了先前报道的具有TDP-43抑制作用的分子3,3'-(吖啶-4,5-二基双(亚甲基))3,3'-(吖啶-4,5-二基双(亚甲基))2(1-(2-乙氧基-2-氧乙基)苯并咪唑-3-ium)二溴盐(AIM4)及其衍生物3,3'-(吖啶-4,5-二基双(亚甲基))和3,3'-(吖啶-4,5-二基双(亚甲基))2(1-(羧甲基)苯并咪唑-3-ium)二溴盐(ABA)的小胶质细胞极化特性。与3,3'-(吖啶-4,5-二基双(亚甲基))双(1-(2-乙氧基-2-氧乙基)苯并咪唑-3-ium)二溴盐(ABA)相比,3,3'-(吖啶-4,5-二基双(亚甲基))双(1-(羧甲基)苯并咪唑-3-ium)二溴盐(AIM4)显示出更强的维持小胶质细胞抗炎状态和TDP-43结合的能力。总亚硝酸盐水平、线粒体膜电位分析和分子对接研究证实了这一点。在所有吖啶衍生物治疗后,选定的促炎细胞因子肿瘤坏死因子-α (TNF-α)和白细胞介素-1β (IL-1β)水平下降,抗炎细胞因子IL-4和IL-10水平升高,但不是非常显著。在脂多糖(LPS)触发的小鼠小胶质细胞和小鼠胚胎上分别研究了这些化合物,结果显示它们没有明显的细胞毒性和生理变化(心律)。在分子对接研究中,TDP-43 315突变为谷氨酸的丙氨酸直接与AIM4相互作用。然而,ABE和ABA中吖啶的芳香主链与TDP-43的313苯基丙氨酸的π-σ相互作用,以及309、310个甘氨酸和咪唑溴侧链之间形成的氢键,使得这些吖啶衍生物与潜在抑制纤维性颤动的蛋白质结合更强。结论:ABA、ABE和AIM4维持小胶质细胞处于抗炎状态。但其与TDP-43的相互作用及其抗炎作用机制还有待进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis.

Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.

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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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