title: MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.
abstract: Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China. Electronic address: quyi712002@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Experimental Medicine, West China First University Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: dezhi.mu@ucsf.edu.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Mu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000254:growth & development*; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D034281:Dynamins / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000517:prevention & control* / Q000523:psychology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D061945:Caspase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C000610381:MLKL protein, rat; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose
keywords: Brain damage; Hypoxia-ischemia; MLKL; Neonate; Neuron