{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:26:23Z","timestamp":1789003583604,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671902"],"award-info":[{"award-number":["81671902"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Project of Tianjin Applied Basic and Cutting-edge Technological Research","award":["17JCYBJC25200"],"award-info":[{"award-number":["17JCYBJC25200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI. Methods: Ten human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL\/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg\/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg\/kg). Results: The expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL\/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047. Conclusions: ER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice.<\/jats:p>","DOI":"10.3390\/jcm11092348","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"2348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Activation of Sigma-1 Receptor Alleviates ER-Associated Cell Death and Microglia Activation in Traumatically Injured Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Mingming","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobin","family":"Min","sequence":"additional","affiliation":[{"name":"Baodi Clinical College, Tianjin Medical University, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Mi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chai","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanglian","family":"Chen","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanjun","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin 300052, China"},{"name":"Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.brainres.2011.01.045","article-title":"Methylprednisolone exacerbates acute critical illness-related corticosteroid insufficiency associated with traumatic brain injury in rats","volume":"1382","author":"Chen","year":"2011","journal-title":"Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1089\/neu.2000.17.927","article-title":"Apoptosis after traumatic brain injury","volume":"17","author":"Raghupathi","year":"2000","journal-title":"J. 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