Zhang Hua-Sheng, Li Hua, Zhang Ding-Ding, Yan Hui-Ying, Zhang Zi-Huan, Zhou Chen-Hui, Ye Zhen-Nan, Chen Qiang, Jiang Tian-Wei, Liu Jing-Peng, Hang Chun-Hua
Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, PR China.
Brain Res. 2016 Jul 15;1643:130-9. doi: 10.1016/j.brainres.2016.05.003. Epub 2016 May 4.
Myeloid differentiation factor 88(MyD88) is an endogenous adaptor protein that plays an important role in coordinating intracellular inflammatory responses induced by agonists of the Toll-like receptor and interleukin-1 receptor families. MyD88 has been reported to be essential for neuronal death in animal models and may represent a therapeutic target for pharmacologic inhibition following traumatic brain injury (TBI). The purpose of the current study was to investigate the neuroprotective effect of MyD88 specific inhibitor ST2825 in an experimental mouse model of TBI. Intracerebroventricular (ICV) injection of high concentration (20μg/μL) ST2825 (15min post TBI) attenuated the development of TBI in mice, markedly improved neurological function and reduced brain edema. Decreased neural apoptosis and increased neuronal survival were also observed. Biochemically, the high concentration of ST2825 significantly reduced the levels of MyD88, further decreased TAK1, p-TAK1, nuclear p65 and increased IκB-α. Additionally, ST2825 significantly reduced the levels of Iba-1 and inflammatory factors TNF-α and IL-1β. These data provide an experimental rationale for evaluation of MyD88 as a drug target and highlight the potential therapeutic implications of ST2825 in TBI.
髓样分化因子88（MyD88）是一种内源性衔接蛋白，在协调由Toll样受体和白细胞介素-1受体家族激动剂诱导的细胞内炎症反应中起重要作用。据报道，MyD88在动物模型的神经元死亡中至关重要，可能是创伤性脑损伤（TBI）后药物抑制的治疗靶点。本研究的目的是在实验性小鼠TBI模型中研究MyD88特异性抑制剂ST2825的神经保护作用。在TBI后15分钟经脑室内（ICV）注射高浓度（20μg/μL）的ST2825可减轻小鼠TBI的发展，显著改善神经功能并减轻脑水肿。还观察到神经细胞凋亡减少和神经元存活率增加。在生化方面，高浓度的ST2825显著降低MyD88水平，进一步降低TAK1、p-TAK1、核p65水平并增加IκB-α。此外，ST2825显著降低Iba-1以及炎症因子TNF-α和IL-1β的水平。这些数据为评估MyD88作为药物靶点提供了实验依据，并突出了ST2825在TBI中的潜在治疗意义。
