The degradation of mixed lineage kinase domain-like protein promotes neuroprotection after ischemic brain injury
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Yanlong Zhou1,2,*, Beiqun Zhou1,3,*, Hui Tu4,*, Yan Tang1, Chen Xu1,5, Yanbo Chen2, Zhong Zhao5 and Zhigang Miao1
1Institute of Neuroscience, Soochow University, Suzhou City, Jiangsu Province, China
2Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, China
3Department of Neurology, The Second Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province, China
4Department of Anesthesia, The Second Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China
5Department of Neurology, The Affiliated Suzhou Hospital, Nanjing Medical University, Suzhou City, Jiangsu Province, China
Zhigang Miao, email: [email protected]
Zhong Zhao, email: [email protected]
Keywords: Necrosulfonamide, MLKL, ischemia reperfusion injury, necrosis
Received: April 11, 2017 Accepted: June 05, 2017 Published: July 18, 2017
Mixed lineage kinase domain-like (MLKL) protein was recently found to play a critical role in necrotic cell death. To explore its role in neurological diseases, we measured MLKL protein expression after ischemia injury in a mouse model. We found that MLKL expression significantly increased 12 h after ischemia/reperfusion (I/R) injury with peak levels at 48 h. Inhibition of MLKL by intraperitoneal administration of NSA significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. Further, we found NSA reduced MLKL levels via the ubiquitination proteasome pathway, but not by inhibiting RNA transcription. Interestingly, NSA administration increased cleaved PARP-1 levels, indicating the protective effects of MLKL inhibition is not related to apoptosis. These findings suggest MLKL is a new therapeutic target for neurological pathologies like stroke. Therefore, promoting degradation of MLKL may be a novel avenue to reduce necrotic cell death after ischemic brain injury.
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