Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, People's Republic of China.
Department of Acupuncture-Moxibustion-Massage, Shaanxi University of Chinese Medicine, Xi'an, 712000, Shaanxi Province, People's Republic of China.
Mol Neurobiol. 2021 Feb;58(2):761-776. doi: 10.1007/s12035-020-02144-5. Epub 2020 Oct 6.
Nod-like receptor protein 3 (NLRP3)-associated neuroinflammation mediated by activated microglia is involved in the pathogenesis of depression. The role of the pore-forming protein gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3 inflammasome mediating inflammatory programmed cell death, in depression has not been well defined. Here, we provide evidence that paeoniflorin (PF), a monoterpene glycoside compound derived from Paeonia lactiflora, ameliorated reserpine-induced mouse depression-like behaviors, characterized as increased mobility time in tail suspension test and forced swimming test, as well as the abnormal alteration of synaptic plasticity in the depressive hippocampus. The molecular docking simulation predicted that PF would interact with C-terminus of GSDMD. We further demonstrated that PF administration inhibited the enhanced expression of GSDMD which mainly distributed in microglia, along with the proteins involved in pyroptosis signaling transduction including caspase (CASP)-11, CASP-1, NLRP3, and interleukin (IL)-1β in the hippocampus of mice treated with reserpine. And also, PF prevented lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-induced pyroptosis in murine N9 microglia in vitro, evidenced by inhibiting the expression of CASP-11, NLRP3, CASP-1 cleavage, as well as IL-1β. Furthermore, VX-765, an effective and selective inhibitor for CASP-1 activation, reduced the expression of inflammasome and pyroptosis-associated proteins in over-activated N9 and also facilitated PF-mediated inhibition of pyroptosis synergistically. Collectively, the data indicated that PF exerted antidepressant effects, alleviating neuroinflammation through inhibiting CASP-11-dependent pyroptosis signaling transduction induced by over-activated microglia in the hippocampus of mice treated with reserpine. Thus, GSDMD-mediated pyroptosis in activated microglia is a previously unrecognized inflammatory mechanism of depression and represents a unique therapeutic opportunity for mitigating depression given PF administration.
Nod-样受体蛋白 3（NLRP3）相关的神经炎症通过激活的小胶质细胞介导与抑郁症的发病机制有关。新近发现的孔形成蛋白 GSDMD（gasdermin D）是 NLRP3 炎性小体下游的炎症程序性细胞死亡的执行者，其在抑郁症中的作用尚未明确。在这里，我们提供的证据表明，芍药苷（PF），一种从芍药中提取的单萜糖苷化合物，改善了利血平诱导的小鼠抑郁样行为，表现为悬尾试验和强迫游泳试验中移动时间增加，以及抑郁海马中突触可塑性的异常改变。分子对接模拟预测 PF 将与 GSDMD 的 C 末端相互作用。我们进一步证明，PF 给药抑制了增强的 GSDMD 表达，主要分布在小胶质细胞中，以及与利血平处理的小鼠海马中细胞焦亡信号转导相关的蛋白质，包括半胱氨酸天冬氨酸蛋白酶（CASP）-11、CASP-1、NLRP3 和白细胞介素（IL）-1β。此外，PF 可预防脂多糖（LPS）和三磷酸腺苷（ATP）诱导的体外小鼠 N9 小胶质细胞细胞焦亡，表现为抑制 CASP-11、NLRP3、CASP-1 切割和 IL-1β的表达。此外，有效且选择性的 CASP-1 激活抑制剂 VX-765 降低了过度激活的 N9 中炎性小体和细胞焦亡相关蛋白的表达，并且还协同促进了 PF 介导的细胞焦亡抑制。综上所述，这些数据表明，PF 通过抑制利血平处理的小鼠海马中过度激活的小胶质细胞中 CASP-11 依赖性细胞焦亡信号转导发挥抗抑郁作用，从而减轻神经炎症。因此，激活的小胶质细胞中 GSDMD 介导的细胞焦亡是一种以前未被认识到的抑郁症炎症机制，代表了一种独特的治疗机会，可通过给予 PF 来减轻抑郁。
