Department of Neurosurgery, The Third People's Hospital of Hubei Province, Wuhan, Hubei, China.
J Biochem Mol Toxicol. 2021 Sep;35(9):e22850. doi: 10.1002/jbt.22850. Epub 2021 Aug 17.
Sodium houttuyfonate (SH) is a chemical compound synthesized by houttuynin and sodium bisulfite. As it has antinflammatory effects, SH has been widely used to treat autoimmune diseases, including post events following traumatic brain injury (TBI). Meanwhile, NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasomes in microglia may play a central role in TBI. But to date, the intracellular mechanisms involved in the anti-inflammatory effects of SH in TBI remain unknown, especially whether regulating NLRP3. To gain an insight into this possibility, we conducted cell culture and biochemical studies on the effect of SH on NLRP3 inflammasome in microglia. The results showed that SH inhibited TLR4 and NLRP3 inflammasome activation in the microglia cell. In parallel, phosphorylation of ERK and NF-κB p65, which play a key role in NLRP3 inflammasome formation, was decreased. Intraperitoneal injection of SH into TBI mice significantly reduced the modified neurological severity score (mNSS), as well as the degree of microglia apoptosis post-controlled cortical impact (CCI). Immunohistochemistry, Western blot analysis, and reverse-transcription polymerase chain reaction (RT-PCR) revealed that SH markedly reduced NLRP3 inflammasome activation, TLR4 activity, phosphorylation of ERK and NF-κB. Moreover, SH significantly inhibited microglia activation post-CCI, but effectively promoted the astrocyte activation and angiopoiesis. Taken together, our research provides evidence that SH attenuated neurological deficits post TBI through inhibiting NLRP3 inflammasome activation, via influencing the TLR4/NF-κB signaling pathway. These findings explain the intracellular mechanism of the anti-inflammatory activity caused by SH treatment following TBI.
荭酮酸钠（SH）是由鱼腥草素和亚硫酸氢钠合成的化合物。由于具有抗炎作用，SH 已被广泛用于治疗自身免疫性疾病，包括创伤性脑损伤（TBI）后的事件。同时，小胶质细胞中的 NOD 样受体含 pyrin 结构域 3（NLRP3）炎性体可能在 TBI 中起核心作用。但迄今为止，SH 治疗 TBI 的抗炎作用的细胞内机制尚不清楚，特别是是否调节 NLRP3。为了深入了解这种可能性，我们对 SH 对小胶质细胞中 NLRP3 炎性体的影响进行了细胞培养和生化研究。结果表明，SH 抑制了小胶质细胞中 TLR4 和 NLRP3 炎性体的激活。同时，NLRP3 炎性体形成的关键作用的 ERK 和 NF-κB p65 的磷酸化减少。SH 腹腔内注射到 TBI 小鼠显著降低了改良神经功能缺损评分（mNSS），以及皮质撞击（CCI）后小胶质细胞凋亡的程度。免疫组织化学、Western blot 分析和逆转录聚合酶链反应（RT-PCR）显示，SH 显著降低 NLRP3 炎性体激活、TLR4 活性、ERK 和 NF-κB 的磷酸化。此外，SH 明显抑制了 CCI 后的小胶质细胞激活，但有效地促进了星形胶质细胞的激活和血管生成。总之，我们的研究提供了证据，表明 SH 通过抑制 NLRP3 炎性体的激活来减轻 TBI 后的神经功能缺损，通过影响 TLR4/NF-κB 信号通路。这些发现解释了 SH 治疗 TBI 后抗炎活性的细胞内机制。
