MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.
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.
['Qu|Yi|Y|', 'Shi|Jing|J|', 'Tang|Ying|Y|', 'Zhao|Fengyan|F|', 'Li|Shiping|S|', 'Meng|Junjie|J|', 'Tang|Jun|J|', 'Lin|Xuemei|X|', 'Peng|Xiaodong|X|', 'Mu|Dezhi|D|']
D000818:Animals D000831:Animals, Newborn D001522:Behavior, Animal D001921:Brain D061945:Caspase Inhibitors D016923:Cell Death D002462:Cell Membrane D034281:Dynamins D005947:Glucose D020925:Hypoxia-Ischemia, Brain D009474:Neurons D047428:Protein Kinase Inhibitors D011494:Protein Kinases D017346:Protein Serine-Threonine Kinases D034741:RNA, Small Interfering D051381:Rats D017207:Rats, Sprague-Dawley D053422:Receptor-Interacting Protein Serine-Threonine Kinases
MLKL Hypoxia-ischemia Neuron Neonate Brain damage