Yu Enxing, Zhang Erjia, Lv Xinhuang, Yan Lin, Lin Zhongxiao, Siaw-Debrah Felix, Zhang Ying, Yang Su, Ruan Linhui, ZhuGe Qichuan, Ni Haoqi
Department of Plastic and Reconstructive Surgery, Ningbo First Hospital, Ningbo, Zhejiang, China.
Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, Wenzhou, Zhejiang, China.
J Neurotrauma. 2023 Apr;40(7-8):742-757. doi: 10.1089/neu.2021.0318. Epub 2022 Sep 9.
Pyroptosis is considered one of a critical factor in the recovery of neurological function following traumatic brain injury. Brain injury activates a molecular signaling cascade associated with pyroptosis and inflammation, including NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we explored the neuroprotective effects of LDC7559, a GSDMD inhibitor. Briefly, LDC7559, siRNA-GSDMD (si-GSDMD), or equal solvent was administrated to mice with a lipopolysaccharide + nigericin (LPS + Nig) model or with controlled cortical impact brain injury. The findings revealed that inflammation and pyroptosis levels were decreased by LDC7559 or si-GSDMD treatment both in and . Immunofluorescence staining, brain water content, hematoxylin and eosin staining, and behavioral investigations suggested that LDC7559 or si-GSDMD inhibited microglial proliferation, ameliorated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. Taken together, LDC7559 may inhibit pyroptosis and reduce inflammation by inhibiting GSDMD, thereby promoting the recovery of neurological function.
焦亡被认为是创伤性脑损伤后神经功能恢复的关键因素之一。脑损伤会激活与焦亡和炎症相关的分子信号级联反应，包括NLRP3、炎性细胞因子、半胱天冬酶-1、gasdermin D（GSDMD）以及其他与焦亡相关的蛋白质。在本研究中，我们探究了GSDMD抑制剂LDC7559的神经保护作用。简而言之，将LDC7559、小干扰RNA-GSDMD（si-GSDMD）或等量溶剂给予脂多糖+尼日利亚菌素（LPS+Nig）模型小鼠或控制性皮质撞击脑损伤小鼠。研究结果显示，LDC7559或si-GSDMD处理均可降低模型小鼠体内的炎症和焦亡水平。免疫荧光染色、脑含水量、苏木精-伊红染色及行为学研究表明，LDC7559或si-GSDMD可抑制小胶质细胞增殖，减轻脑水肿，减少脑组织损失，并促进脑功能恢复。综上所述，LDC7559可能通过抑制GSDMD来抑制焦亡并减轻炎症，从而促进神经功能恢复。
