{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T08:10:50Z","timestamp":1783671050820,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea","award":["2018R1C1B6006159"],"award-info":[{"award-number":["2018R1C1B6006159"]}]},{"name":"National Research Foundation of Korea","award":["2020R1A2C2008480"],"award-info":[{"award-number":["2020R1A2C2008480"]}]},{"name":"National Research Foundation of Korea","award":["2018R1D1A2B07049888"],"award-info":[{"award-number":["2018R1D1A2B07049888"]}]},{"name":"Yonsei University College of Medicine","award":["6-2019-0188"],"award-info":[{"award-number":["6-2019-0188"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sudden cardiac arrest leads to a significantly increased risk of severe neurological impairment and higher mortality rates in survivors due to global brain tissue injury caused by prolonged whole-body ischemia and reperfusion. The brain undergoes various deleterious cascading events. Among these damaging mechanisms, neuroinflammation plays an especially crucial role in the exacerbation of brain damage. Clinical guidelines indicate that 33 \u00b0C and 36 \u00b0C are both beneficial for targeted temperature management (TTM) after cardiac arrest. To clarify the mechanistic relationship between TTM and inflammation in transient global ischemia (TGI) and determine whether 36 \u00b0C produces a neuroprotective effect comparable to 33 \u00b0C, we performed an experiment using a rat model. We found that TTM at 36 \u00b0C and at 33 \u00b0C attenuated neuronal cell death and apoptosis, with significant improvements in behavioral function that lasted for up to 72 h. TTM at 33 \u00b0C and 36 \u00b0C suppressed the propagation of inflammation including the release of high mobility group box 1 from damaged cells, the activation and polarization of the microglia, and the excessive release of activated microglia-induced inflammatory cytokines. There were equal neuroprotective effects for TTM at 36 \u00b0C and 33 \u00b0C. In addition, hypothermic complications and should be considered safe and effective after cardiac arrest.<\/jats:p>","DOI":"10.3390\/ijms22105114","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T10:59:12Z","timestamp":1620817152000},"page":"5114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Transient Global Ischemia-Induced Brain Inflammatory Cascades Attenuated by Targeted Temperature Management"],"prefix":"10.3390","volume":"22","author":[{"given":"Dae Ki","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1543-4664","authenticated-orcid":false,"given":"Yoo Seok","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Severance Hospital 50, College of Medicine, Yonsei University, Yonsei-ro, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Sun","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Gangnam Severance Hospital 211, College of Medicine, Yonsei University, Eonju-ro, Seoul 06273, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Gangnam Severance Hospital 211, College of Medicine, Yonsei University, Eonju-ro, Seoul 06273, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Ho","family":"Beom","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Severance Hospital 50, College of Medicine, Yonsei University, Yonsei-ro, Seoul 03722, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3074-011X","authenticated-orcid":false,"given":"Sung Phil","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Gangnam Severance Hospital 211, College of Medicine, Yonsei University, Eonju-ro, Seoul 06273, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2074-6745","authenticated-orcid":false,"given":"Je Sung","family":"You","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Gangnam Severance Hospital 211, College of Medicine, Yonsei University, Eonju-ro, Seoul 06273, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Won","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1161\/CIR.0000000000000313","article-title":"Temperature management after cardiac arrest: An advisory statement by the advanced life support task force of the international liaison committee on resuscitation and the american heart association emergency cardiovascular care committee and the council on cardiopulmonary, critical care, perioperative and resuscitation","volume":"132","author":"Donnino","year":"2015","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1136\/heartjnl-2015-307450","article-title":"Post-resuscitation care following out-of-hospital and in-hospital cardiac arrest","volume":"101","author":"Girotra","year":"2015","journal-title":"Heart"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"173","DOI":"10.4266\/acc.2019.00654","article-title":"Management of post-cardiac arrest syndrome","volume":"34","author":"Kang","year":"2019","journal-title":"Acute Crit. Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S0196-0644(00)82028-4","article-title":"Molecular mechanisms of ischemic neuronal injury","volume":"36","author":"Neumar","year":"2000","journal-title":"Ann. Emerg. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrn3174","article-title":"Neuroprotective mechanisms of hypothermia in brain ischaemia","volume":"13","author":"Yenari","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1161\/STROKEAHA.117.017286","article-title":"Targeting reperfusion injury in the age of mechanical thrombectomy","volume":"49","author":"Mizuma","year":"2018","journal-title":"Stroke"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"(2002). Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med., 346, 549\u2013556.","DOI":"10.1056\/NEJMoa012689"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1056\/NEJMoa1310519","article-title":"Targeted temperature management at 33 \u00b0C versus 36 \u00b0C after cardiac arrest","volume":"369","author":"Nielsen","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1097\/SHK.0000000000001106","article-title":"Targeted Temperature Management at 33 \u00b0C or 36 \u00b0C Produces equivalent neuroprotective effects in the middle cerebral artery occlusion rat model of ischemic stroke","volume":"50","author":"Lee","year":"2018","journal-title":"Shock"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.neuropharm.2017.08.025","article-title":"Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise","volume":"134","author":"Kurisu","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev-immunol-030409-101323","article-title":"HMGB1 is a therapeutic target for sterile inflammation and infection","volume":"29","author":"Andersson","year":"2011","journal-title":"Ann. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1523\/JNEUROSCI.3815-05.2006","article-title":"HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain","volume":"26","author":"Kim","year":"2006","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13041-016-0260-0","article-title":"Hypothermia inhibits the propagation of acute ischemic injury by inhibiting HMGB1","volume":"9","author":"Lee","year":"2016","journal-title":"Molec. Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fncel.2019.00127","article-title":"The role of high mobility group box 1 in ischemic stroke","volume":"13","author":"Ye","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1080\/01616412.2018.1454090","article-title":"Mild focal hypothermia regulates the dynamic polarization of microglia after ischemic stroke in mice","volume":"40","author":"Liu","year":"2018","journal-title":"Neurol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.nbd.2016.09.013","article-title":"Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice","volume":"96","author":"Lee","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1177\/0271678X16680003","article-title":"Posttraumatic therapeutic hypothermia alters microglial and macrophage polarization toward a beneficial phenotype","volume":"37","author":"Truettner","year":"2017","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrneurol.2014.207","article-title":"Microglial and macrophage polarization\u2014new prospects for brain repair","volume":"11","author":"Hu","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Karuppagounder, V., Giridharan, V.V., Arumugam, S., Sreedhar, R., Palaniyandi, S.S., Krishnamurthy, P., Quevedo, J., Watanabe, K., Konishi, T., and Thandavarayan, R.A. (2016). Modulation of macrophage polarization and HMGB1-TLR2\/TLR4 cascade plays a crucial role for cardiac remodeling in senescence-accelerated prone mice. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152922"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"506","DOI":"10.3389\/fncel.2019.00506","article-title":"High-mobility group box 1 contributes to cerebral cortex injury in a neonatal hypoxic-ischemic rat model by regulating the phenotypic polarization of microglia","volume":"13","author":"Sun","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.281.5381.1309","article-title":"Mitochondria and apoptosis","volume":"281","author":"Green","year":"1998","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1126\/science.281.5381.1305","article-title":"Death receptors: Signaling and modulation","volume":"281","author":"Ashkenazi","year":"1998","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1038\/jcbfm.2008.64","article-title":"Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse","volume":"28","author":"Ferenczi","year":"2008","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1742-2094-11-26","article-title":"CX3CR1 deficiency suppresses activation and neurotoxicity of microglia\/macrophage in experimental ischemic stroke","volume":"11","author":"Tang","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C135","DOI":"10.1152\/ajpcell.00136.2018","article-title":"Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke","volume":"316","author":"Yang","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1046\/j.0953-816x.2001.01838.x","article-title":"Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia","volume":"15","author":"Rivera","year":"2002","journal-title":"Eur. J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/(SICI)1098-1136(200004)30:2<199::AID-GLIA9>3.0.CO;2-#","article-title":"Differential regulation of tissue inhibitor of metalloproteinase mRNA expression in response to intracranial injury","volume":"30","author":"Jaworski","year":"2000","journal-title":"Glia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2565","article-title":"Regulation of innate immune responses in the brain","volume":"9","author":"Rivest","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","first-page":"378","article-title":"Microglial activation in stroke: Therapeutic targets","volume":"7","author":"Yenari","year":"2010","journal-title":"Neurother. J. Am. Soc. Exp. NeuroTher."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/cns.12360","article-title":"Mechanisms and potential therapeutic applications of microglial activation after brain injury","volume":"21","author":"Kim","year":"2015","journal-title":"CNS Neurosci. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1046\/j.1471-4159.2003.01977.x","article-title":"Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and ischaemic brain damage in the endothelin-1 rat model for focal cerebral ischaemia","volume":"87","author":"Vermijlen","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nm.2399","article-title":"The immunology of stroke: From mechanisms to translation","volume":"17","author":"Iadecola","year":"2011","journal-title":"Nat. Med."},{"key":"ref_34","first-page":"5","article-title":"Induced Hypothermia in Neurocritical Care: A Review","volume":"49","author":"Cook","year":"2017","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nrneurol.2012.21","article-title":"Hypothermia for acute brain injury\u2013mechanisms and practical aspects","volume":"8","author":"Choi","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/jcbfm.1992.34","article-title":"Global cerebral ischemia associated with cardiac arrest in the rat: I. Dynamics of early neuronal changes","volume":"12","author":"Kawai","year":"1992","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hong, D.K., Kho, A.R., Lee, S.H., Jeong, J.H., Kang, B.S., Kang, D.H., Park, M.K., Park, K.H., Lim, M.S., and Choi, B.Y. (2020). Transient receptor potential melastatin 2 (TRPM2) inhibition by antioxidant, N-Acetyl-l-Cysteine, reduces global cerebral ischemia-induced neuronal death. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176026"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kho, A.R., Choi, B.Y., Lee, S.H., Hong, D.K., Lee, S.H., Jeong, J.H., Park, K.H., Song, H.K., Choi, H.C., and Suh, S.W. (2018). Effects of protocatechuic acid (PCA) on global cerebral ischemia-induced hippocampal neuronal death. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051420"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/nprot.2009.125","article-title":"The adhesive removal test: A sensitive method to assess sensorimotor deficits in mice","volume":"4","author":"Bouet","year":"2009","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5114\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:59:45Z","timestamp":1760162385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,12]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22105114"],"URL":"https:\/\/doi.org\/10.3390\/ijms22105114","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,12]]}}}