Du Li-Xia, Gao Xin-Yi, Ren Xue-Qi, Yang Ya-Yue, Ding Yang-Yang, Xu Ao, Wang Xiao-Yu, Zhang Yu-Xin, Shu Shi, Yang Yu-Fang, Mi Wen-Li, Wang Zhi-Fei
Department of Biochemistry, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Acta Pharmacol Sin. 2025 Feb;46(2):366-379. doi: 10.1038/s41401-024-01386-6. Epub 2024 Sep 16.
Chronic itch is a maladaptive and debilitating symptom in patients with allergic contact dermatitis (ACD), adversely affecting their quality of life. There is a lack of effective treatments for ACD-associated uncontrollable itch. In this study, we explored the antipruritic effects of baicalein (BE), a bioactive flavonoid extracted from the root of Scutellaria baicalensis Georgi, and the underlying mechanisms in alleviating chronic itch triggered by diphenylcyclopropenone (DCP) in a mouse model of ACD. The ACD mice were intraperitoneally injected with BE (5, 30, and 60 mg·kg·d) for 7 days during the DCP challenge phase. The results showed that DCP-treated mice exhibited severe spontaneous scratching behaviors that was reduced after BE injections in a dose-dependent manner accompanied by inhibition of spinal astrocyte activation. We observed that the spinal astrocytic STAT3-LCN2 cascade plays a crucial role in controlling the activation of astrocytes in chronic itch. Intrathecal injection of the STAT3 inhibitor AG490 or Lcn2 siRNA significantly reduced scratching behavior and astrocyte activation in ACD mice. Moreover, BE markedly attenuated the increased phosphorylation of STAT3 (p-STAT3) and LCN2 expression in the spinal cords of ACD mice and in lipopolysaccharide-stimulated primary spinal astrocytes. Altogether, BE relieved chronic itch by suppressing the spinal astrocytic STAT3-LCN2 cascade. These findings provide a potential avenue for the management of chronic itch. Schematic summary of the main findings illustrating that BE alleviates chronic itch through suppressing the spinal astrocytic STAT3-LCN2 cascade. Specifically, BE suppresses the expression of p-STAT3 to inhibit the reactive state of astrocytes in spinal dorsal horn, and then decreases the expression of astrocytic LCN2 to alleviate chronic itch in ACD mice.
慢性瘙痒是过敏性接触性皮炎（ACD）患者的一种适应不良且使人衰弱的症状，会对他们的生活质量产生不利影响。目前缺乏针对ACD相关的难以控制的瘙痒的有效治疗方法。在本研究中，我们探究了黄芩素（BE）的止痒作用及其在减轻ACD小鼠模型中由二苯环丙烯酮（DCP）引发的慢性瘙痒的潜在机制。BE是从黄芩根中提取的一种生物活性黄酮类化合物。在DCP激发阶段，对ACD小鼠腹腔注射BE（5、30和60mg·kg·d），持续7天。结果显示，DCP处理的小鼠表现出严重的自发搔抓行为，而BE注射后这种行为以剂量依赖的方式减少，同时伴有脊髓星形胶质细胞活化的抑制。我们观察到脊髓星形胶质细胞的STAT3-LCN2级联在控制慢性瘙痒中星形胶质细胞的活化方面起关键作用。鞘内注射STAT3抑制剂AG490或Lcn2 siRNA可显著降低ACD小鼠的搔抓行为和星形胶质细胞活化。此外，BE显著减弱了ACD小鼠脊髓以及脂多糖刺激的原代脊髓星形胶质细胞中STAT3的磷酸化增加（p-STAT3）和LCN2的表达。总之，BE通过抑制脊髓星形胶质细胞的STAT3-LCN2级联来缓解慢性瘙痒。这些发现为慢性瘙痒的治疗提供了一条潜在途径。主要研究结果的示意图总结表明，BE通过抑制脊髓星形胶质细胞的STAT3-LCN2级联来减轻慢性瘙痒。具体而言，BE抑制p-STAT3的表达以抑制脊髓背角星形胶质细胞的反应状态，进而降低星形胶质细胞LCN2的表达以减轻ACD小鼠的慢性瘙痒。
