PMID- 30851432 OWN - NLM STAT- MEDLINE DCOM- 20191224 LR - 20211204 IS - 1095-9564 (Electronic) IS - 1074-7427 (Linking) VI - 161 DP - 2019 May TI - Salubrinal offers neuroprotection through suppressing endoplasmic reticulum stress, autophagy and apoptosis in a mouse traumatic brain injury model. PG - 12-25 LID - S1074-7427(19)30048-6 [pii] LID - 10.1016/j.nlm.2019.03.002 [doi] AB - Traumatic brain injury (TBI) is a complex injury that can cause severe disabilities and even death. TBI can induce secondary injury cascades, including but not limited to endoplasmic reticulum (ER) stress, apoptosis and autophagy. Although the investigators has previously shown that salubrinal, the selective phosphatase inhibitor of p-eIF2alpha, ameliorated neurologic deficits in murine TBI model, the neuroprotective mechanisms of salubrinal need further research to warrant the preclinical value. This study was undertaken to characterize the effects of salubrinal on cell death and neurological outcomes following TBI in mice and the potential mechanisms. In the current study, ER stress-related proteins including p-eIF2alpha, GRP78 and CHOP showed peak expressions both in the cortex and hippocampus from day 2 to day 3 after TBI, indicating ER stress was activated in our TBI model. Immunofluorescence staining showed that CHOP co-located NeuN-positive neuron, GFAP-positive astrocyte, Iba-1-positive microglia, CD31-positive vascular endothelial cell and PDGFR-beta-positive pericyte in the cortex on day 2 after TBI, and these cells mentioned above constitute the neurovascular unit (NVU). We also found TBI-induced plasmalemma permeability, motor dysfunction, spatial learning and memory deficits and brain lesion volume were alleviated by continuous intraperitoneal administration of salubrinal post TBI. To investigate the underlying mechanisms further, we determined that salubrinal suppressed the expression of ER stress, autophagy and apoptosis related proteins on day 2 after TBI. In addition, salubrinal administration decreased the number of CHOP+/TUNEL+ and CHOP+/LC3+ cells on day 2 after TBI, detected by immunofluorescence. In conclusion, these data imply that salubrinal treatment improves morphological and functional outcomes caused by TBI in mice and these neuroprotective effects may be associated with inhibiting apoptosis, at least in part by suppressing ER stress-autophagy pathway. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Wang, Zu-Feng AU - Wang ZF AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Gao, Cheng AU - Gao C AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Chen, Wei AU - Chen W AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Gao, Yuan AU - Gao Y AD - Department of Forensic Medicine, Wenzhou Medical University, Wenzhou 325035, China. FAU - Wang, Hao-Chen AU - Wang HC AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Meng, Ying AU - Meng Y AD - Community Health Center, Suzhou Western Eco-City, Suzhou 215161, China. FAU - Luo, Cheng-Liang AU - Luo CL AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Zhang, Ming-Yang AU - Zhang MY AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Chen, Guang AU - Chen G AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Chen, Xi-Ping AU - Chen XP AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. FAU - Wang, Tao AU - Wang T AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China; Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai 200063, China. Electronic address: taowang@suda.edu.cn. FAU - Tao, Lu-Yang AU - Tao LY AD - Department of Forensic Medicine, Medical School of Soochow University, Suzhou 215123, China. Electronic address: taoluyang@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190306 PL - United States TA - Neurobiol Learn Mem JT - Neurobiology of learning and memory JID - 9508166 RN - 0 (Cinnamates) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Hspa5 protein, mouse) RN - 0 (Neuroprotective Agents) RN - 0 (salubrinal) RN - GYV9AM2QAG (Thiourea) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Autophagy/*drug effects MH - Brain Injuries, Traumatic/*drug therapy MH - Cinnamates/*pharmacology MH - Disease Models, Animal MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/*drug effects MH - Male MH - Mice MH - Mice, Inbred ICR MH - Neuroprotective Agents/*pharmacology MH - Thiourea/*analogs & derivatives/pharmacology OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Endoplasmic reticulum stress OT - Salubrinal OT - Traumatic brain injury EDAT- 2019/03/10 06:00 MHDA- 2019/12/25 06:00 CRDT- 2019/03/10 06:00 PHST- 2018/02/21 00:00 [received] PHST- 2019/02/17 00:00 [revised] PHST- 2019/03/05 00:00 [accepted] PHST- 2019/03/10 06:00 [pubmed] PHST- 2019/12/25 06:00 [medline] PHST- 2019/03/10 06:00 [entrez] AID - S1074-7427(19)30048-6 [pii] AID - 10.1016/j.nlm.2019.03.002 [doi] PST - ppublish SO - Neurobiol Learn Mem. 2019 May;161:12-25. doi: 10.1016/j.nlm.2019.03.002. Epub 2019 Mar 6.