Flavonoids as positive allosteric modulators of α7 nicotinic receptors
Flavonoids as positive allosteric modulators of α7 nicotinic receptors
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DOI：
10.1016/j.neuropharm.2019.107794
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发表时间：
2019-12-01
影响因子：
4.7
通讯作者：
Bouzat, Cecilia
中科院分区：
文献类型：
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作者：
Elizabeth Nielsen, Beatriz;Bermudez, Isabel;Bouzat, Cecilia
α 7烟碱受体的正变构调节剂（PAM）的使用是用于神经变性、炎性和认知障碍的有希望的疗法。黄酮类化合物是多酚类化合物，具有神经保护、抗炎和促认知作用。除了众所周知的抗氧化活性外，类黄酮还能触发细胞内途径，并与包括α 7在内的受体相互作用。为了揭示黄酮类化合物的有益作用如何与α 7功能相关联，我们评估了三种代表性黄酮类化合物-染料木黄酮，槲皮素和nephalocyanin 5，7-二羟基-4-苯基香豆素-对全细胞和单通道电流的影响。所有黄酮类化合物增加最大电流引起的乙酰胆碱与最小的影响脱敏，不重新激活脱敏受体，与I型PAM的行为一致。在单通道水平，它们增加开放状态的持续时间，并在长时间发作中产生激活，其功效的等级顺序为染料木黄酮>槲皮素>=奈替米。通过使用突变体和嵌合α 7受体，我们证明了类黄酮与其他PAM共享跨膜结构决定簇。类黄酮的α 7-PAM活性导致细胞活性氧水平降低。因此，α 7的变构增强可能是类黄酮神经保护作用的另一机制，类黄酮可用作设计新治疗剂的支架。
The use of positive allosteric modulators (PAM) of alpha 7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including alpha 7. To reveal how the beneficial actions of flavonoids are linked to alpha 7 function, we evaluated the effects of three representative flavonoids -genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarin- on whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in long-duration episodes with a rank order of efficacy of genistein > quercetin >= neoflavonoid. By using mutant and chimeric alpha 7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The alpha 7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of alpha 7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.