去甲肾上腺素(NA),一种压力荷尔蒙,可以通过与黑素细胞干细胞(McSCs)上的β2肾上腺素能受体(β2AR)结合来加速头发变白。由此,NA-β2AR轴可能是防止应激效应的潜在靶标。然而,鉴定β2AR的选择性阻断剂一直是一个关键挑战。因此,在这项研究中,先进的计算机辅助药物设计(CADD)技术被用来筛选天然分子,导致钩藤碱作为一种有前途的化合物的发现。钩藤碱在β2AR的活性位点内表现出强而稳定的结合,通过分子对接和动态模拟试验验证。当施用于细胞时,钩藤碱有效抑制NA-β2AR信号传导。这种干预导致在应激诱导的小鼠模型中头发变白的显著减少,从28.5%到8.2%。为了更深入地了解潜在的机制,采用转录组测序,这表明NA可能通过影响细胞内钙平衡和促进细胞凋亡来破坏黑素生成。重要的是,钩藤碱是这些下游途径的有效抑制剂。总之,研究表明,钩藤碱通过靶向β2AR来减轻NA对黑素生成的负面影响,从而提供了一个有希望的解决方案,防止压力引起的头发变白。
Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to β2 adrenergic receptors (β2AR) on melanocyte stem cells (McSCs). From this, NA-β2AR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for β2AR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of
rhynchophylline as a promising compound.
Rhynchophylline exhibited strong and stable binding within the active site of β2AR, as verified by molecular docking and dynamic simulation assays. When administered to cells,
rhynchophylline effectively inhibited NA-β2AR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly,
rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that
rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting β2AR, thus offering a promising solution for preventing stress-induced hair graying.