title: Inhibition of myeloid differentiation factor 88(MyD88) by ST2825 provides neuroprotection after experimental traumatic brain injury in mice.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Hua-Sheng
authors.initials: HS
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Ding-Ding
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Zhongdu Hospital, Bengbu, Anhui Province, PR China.
authors.forename: Zi-Huan
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Chen-Hui
authors.initials: CH
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Zhen-Nan
authors.initials: ZN
authors.lastname: Ye
authors.affiliation: Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Tian-Wei
authors.initials: TW
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China.
authors.forename: Jing-Peng
authors.initials: JP
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China; Department of Neurosurgery, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, PR China. Electronic address: hang_neurosurgery@163.com.
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Hang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D013141:Spiro Compounds / Q000008:administration & dosage*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D006574:Heterocyclic Compounds, 2-Ring; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D018696:Neuroprotective Agents; D013141:Spiro Compounds; D062826:Zonula Occludens-1 Protein; D000099151:MAP Kinase Kinase Kinase 7; C507780:Myd88 protein, mouse; C525002:ST2825; C569043:Tjp1 protein, mouse
keywords: Apoptosis; Myeloid differentiation factor 88; ST2825; Traumatic brain injury