选择性非甾体 ERβ 激动剂 AC-186 抑制神经炎症和神经元损伤

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-10-03 DOI:10.1007/s00011-024-01952-y
Folashade O Katola, Misturah Y Adana, Olumayokun A Olajide
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引用次数: 0

摘要

背景:AC-186(4-[4-4-二氟-1-(2-氟苯基)环己基]苯酚)是一种具有神经保护作用的非甾体选择性雌激素受体调节剂。本研究探讨了抑制神经炎症是否有助于该化合物的神经保护活性:方法:在LPS(100 ng/mL)刺激前,用AC-186(0.65-5 μM)处理BV-2小胶质细胞。然后评估促炎介质和蛋白质的水平:结果:用 AC-186 处理 LPS 激活的 BV-2 小胶质细胞可显著降低 iNOS 和 COX-2 的水平(p 2)。进一步研究表明,AC-186 降低了 LPS 诱导的磷酸-p65、磷酸-IκBα 和乙酰-p65 蛋白水平的升高,同时阻断了 NF-κB 的 DNA 结合和荧光素酶活性。AC-186对NF-κB有明显的诱导作用:本研究证实,AC-186 可产生 NF-κB 介导的抗炎活性,这被认为是其神经保护作用的一个促成机制。有人认为,该化合物的抗炎活性与其对 ERβ 的激动作用有关。
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Inhibition of neuroinflammation and neuronal damage by the selective non-steroidal ERβ agonist AC-186.

Background: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.

Methods: BV-2 microglia were treated with AC-186 (0.65-5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.

Results: Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.

Conclusions: This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.

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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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