title: TGFβ-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage.
abstract: Accumulating evidence suggests that activation of mitogen-activated protein kinases (MAPKs) and nuclear factor NF-κB exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking proapoptotic and proinflammatory cellular signaling. Here we evaluate the role of TGFβ-activated kinase 1 (TAK1), a critical regulator of the NF-κB and MAPK pathways, in early brain injury following SAH. Although the expression level of TAK1 did not present significant alternation in the basal temporal lobe after SAH, the expression of phosphorylated TAK1 (Thr-187, p-TAK1) showed a substantial increase 24 h post-SAH. Intracerebroventricular injection of a selective TAK1 inhibitor (10 min post-SAH), 5Z-7-oxozeaenol (OZ), significantly reduced the levels of TAK1 and p-TAK1 at 24 h post-SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that OZ inhibited SAH-induced phosphorylation of p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Furthermore, OZ administration diminished the SAH-induced apoptosis and EBI. As a result, neurological deficits caused by SAH were reversed. Our findings suggest that TAK1 inhibition confers marked neuroprotection against EBI following SAH. Therefore, TAK1 might be a promising new molecular target for the treatment of SAH.
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Dingding
authors.initials: D
authors.lastname: Zhang
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yan
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Rd., Nanjing 210093, Jiangsu Province, and.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Zong
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: the Department of Neurosurgery, School of Medicine, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Yang
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province.
authors.forename: Mengliang
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 22 Hankou Rd., Nanjing 210093, Jiangsu Province, and likuanyu@nju.edu.cn.
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
authors.affiliation: From the Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province, the Department of Neurosurgery, School of Medicine, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Rd., Nanjing 210002, Jiangsu Province, China hang_neurosurgery@163.com.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Hang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020214:Cerebrovascular Trauma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007276:Injections, Intraventricular; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020672:I-kappa B Proteins; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D000072000:NF-KappaB Inhibitor alpha; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D015025:Zearalenone; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C000606206:Nfkbia protein, rat; C498145:Rela protein, rat
keywords: 5Z-7-oxozeaenol; NF-κB (NF-KB); TAK1; apoptosis; brain; mitogen-activated protein kinase (MAPK); neuroprotection; subarachnoid hemorrhage