Lv Qingchen, Hong Fei, Sun Zhanyuan, Shen Haiyan, Lu Hongyi, Jin Ye, Mao Liming, Song Lei
Department of Pediatrics, Nantong First People's Hospital (The Second Affiliated Hospital of Nantong University), Nantong, Jiangsu 226001, China.
College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
J Neuroimmunol. 2025 Oct 15;407:578701. doi: 10.1016/j.jneuroim.2025.578701. Epub 2025 Jul 22.
Hypoxic-ischemic brain injury (HIBD) represents a primary cause of neurological impairment in neonates and is frequently associated with persistent cognitive and motor deficits. This study explores the regulatory function of optic atrophy 1 (OPA1) in modulating NLRP3 inflammasome-mediated neuroinflammation in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE), and evaluates the impact of the OPA1 inhibitor MYLS22 on neuroinflammatory responses and cerebral injury.
Neonatal rats were subjected to HIBD. Temporal expression patterns of OPA1 and inflammasome-associated proteins were assessed using Western blotting, immunofluorescence, and histopathological analyses. The influence of MYLS22 treatment on neuroinflammatory markers, brain pathology, and cognitive outcomes was also investigated.
HIBD led to a marked reduction in long-form OPA1 (L-OPA1) expression and a concomitant increase in short-form OPA1 (S-OPA1). Activation of the NLRP3 inflammasome peaked between 24 and 48 h post-injury. Treatment with MYLS22 suppressed OPA1 expression in a dose-dependent manner, further enhancing inflammasome activation and aggravating brain injury, characterized by enlarged infarct volumes, increased edema, and impaired cognitive performance. Conversely, in vitro overexpression of L-OPA1 attenuated inflammasome activation and reduced microglial inflammation following ischemia/reperfusion insult, indicating a neuroprotective effect.
These findings demonstrate a pivotal role for OPA1 in controlling neuroinflammation and mitochondrial integrity in the context of HIE. Modulation of OPA1 expression or targeting inflammasome signaling may represent promising therapeutic strategies to alleviate neuroinflammatory injury and improve neurological outcomes in neonates.
缺氧缺血性脑损伤（HIBD）是新生儿神经功能障碍的主要原因，常伴有持续的认知和运动缺陷。本研究在新生大鼠缺氧缺血性脑病（HIE）模型中探讨视神经萎缩蛋白1（OPA1）在调节NLRP3炎性小体介导的神经炎症中的调控作用，并评估OPA1抑制剂MYLS22对神经炎症反应和脑损伤的影响。
对新生大鼠进行HIBD造模。采用蛋白质免疫印迹法、免疫荧光法和组织病理学分析评估OPA1和炎性小体相关蛋白的时间表达模式。还研究了MYLS22治疗对神经炎症标志物、脑病理学和认知结果的影响。
HIBD导致长形式OPA1（L-OPA1）表达显著降低，同时短形式OPA1（S-OPA1）增加。NLRP3炎性小体的激活在损伤后24至48小时达到峰值。MYLS22治疗以剂量依赖性方式抑制OPA1表达，进一步增强炎性小体激活并加重脑损伤，表现为梗死体积增大、水肿增加和认知功能受损。相反，L-OPA1的体外过表达减弱了炎性小体激活，并减少了缺血/再灌注损伤后的小胶质细胞炎症，表明具有神经保护作用。
这些发现表明OPA1在HIE背景下控制神经炎症和线粒体完整性方面起着关键作用。调节OPA1表达或靶向炎性小体信号通路可能是减轻神经炎症损伤和改善新生儿神经功能结局的有前景的治疗策略。
