{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:35:30Z","timestamp":1787027730419,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"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":["81801298"],"award-info":[{"award-number":["81801298"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["YG2023QNB10"],"award-info":[{"award-number":["YG2023QNB10"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["RJTJ22-MS-011"],"award-info":[{"award-number":["RJTJ22-MS-011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["BK20201402"],"award-info":[{"award-number":["BK20201402"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["81801298"],"award-info":[{"award-number":["81801298"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["YG2023QNB10"],"award-info":[{"award-number":["YG2023QNB10"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["RJTJ22-MS-011"],"award-info":[{"award-number":["RJTJ22-MS-011"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["BK20201402"],"award-info":[{"award-number":["BK20201402"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NSFC Promotion Program of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","award":["81801298"],"award-info":[{"award-number":["81801298"]}]},{"name":"NSFC Promotion Program of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","award":["YG2023QNB10"],"award-info":[{"award-number":["YG2023QNB10"]}]},{"name":"NSFC Promotion Program of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","award":["RJTJ22-MS-011"],"award-info":[{"award-number":["RJTJ22-MS-011"]}]},{"name":"NSFC Promotion Program of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine","award":["BK20201402"],"award-info":[{"award-number":["BK20201402"]}]},{"name":"Natural Science Foundation of the Jiangsu Province of China","award":["81801298"],"award-info":[{"award-number":["81801298"]}]},{"name":"Natural Science Foundation of the Jiangsu Province of China","award":["YG2023QNB10"],"award-info":[{"award-number":["YG2023QNB10"]}]},{"name":"Natural Science Foundation of the Jiangsu Province of China","award":["RJTJ22-MS-011"],"award-info":[{"award-number":["RJTJ22-MS-011"]}]},{"name":"Natural Science Foundation of the Jiangsu Province of China","award":["BK20201402"],"award-info":[{"award-number":["BK20201402"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Increasing evidence has demonstrated that ischemic preconditioning (IPC) increases cerebral tolerance to subsequent prolonged ischemic insults. However, the exact mechanisms underlying the process have not been fully explored. In the current study, we aim to investigate whether NLRP3 inflammasome and cell pyroptosis are involved in the neuroprotective mechanism of IPC after ischemic stroke. In vitro, IPC was set up by exposing BV-2 cells to 10 min of oxygen\u2013glucose deprivation (OGD). In vivo, IPC was performed by a transient cerebral ischemia of 10 min occlusion of the middle cerebral artery (MCA) in mice. We found that the NLRP3 inflammasome was activated and cell pyroptosis was induced at 6 h and 24 h post-stroke in an ischemic brain. IPC treatment increased cell viability under OGD state, reduced the infarct size, and attenuated the neurological deficits of mice. However, the effects NLRP3 inflammasome activation and pyroptosis after stroke were attenuated by IPC, which decreased the expression of NLRP3, ASC, cleaved caspase 1, and GSDMD-N and reduced the production of IL-1\u03b2 and IL-18. In addition, confocal immunofluorescence staining of Annexin V-mCherry and SYTOX green was inhibited by IPC. These findings suggest a more enhanced link between IPC and inflammatory signature and cell death, highlighting that the NLRP3 inflammasome may act as a promising target for the prevention and treatment of ischemic stroke.<\/jats:p>","DOI":"10.3390\/brainsci13060897","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T02:41:35Z","timestamp":1685673695000},"page":"897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Ischemic Preconditioning Provides Neuroprotection by Inhibiting NLRP3 Inflammasome Activation and Cell Pyroptosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Li","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meibo","family":"Pan","sequence":"additional","affiliation":[{"name":"Department Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-489X","authenticated-orcid":false,"given":"Wenrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2454-2173","authenticated-orcid":false,"given":"Desheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjiao","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6381-9783","authenticated-orcid":false,"given":"Yinfeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangtai","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrn1927","article-title":"Cerebral preconditioning and ischaemic tolerance","volume":"7","author":"Gidday","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113142","DOI":"10.1016\/j.expneurol.2019.113142","article-title":"Ischemic preconditioning provides long-lasting neuroprotection against ischemic stroke: The role of Nrf2","volume":"325","author":"Yang","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1212\/WNL.0000000000007732","article-title":"Changes in cerebral autoregulation and blood biomarkers after remote ischemic preconditioning","volume":"93","author":"Guo","year":"2019","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1161\/STROKEAHA.111.626911","article-title":"Sphingosine kinase 2 mediates cerebral preconditioning and protects the mouse brain against ischemic injury","volume":"43","author":"Yung","year":"2012","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/nrn3638","article-title":"Inflammasomes in the CNS","volume":"15","author":"Walsh","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-mediated programmed necrotic cell death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends. Biochem. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"732933","DOI":"10.3389\/fimmu.2021.732933","article-title":"NLRP3 inflammasome: Checkpoint connecting innate and adaptive immunity in autoimmune diseases","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108053","DOI":"10.1016\/j.pharmthera.2021.108053","article-title":"Targeting the NLRP3 inflammasome in cardiovascular diseases","volume":"236","author":"Toldo","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"434","DOI":"10.4103\/1673-5374.346468","article-title":"The Alzheimer\u2019s disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation","volume":"18","author":"Wang","year":"2023","journal-title":"Neural. Regen. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gustin, A., Kirchmeyer, M., Koncina, E., Felten, P., Losciuto, S., Heurtaux, T., Tardivel, A., Heuschling, P., and Dostert, C. (2015). NLRP3 inflammasome is expressed and functional in mouse brainmicroglia but not in astrocytes. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130624"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e790","DOI":"10.1038\/cddis.2013.326","article-title":"Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke","volume":"4","author":"Fann","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.bbi.2020.12.009","article-title":"The NLRP3 inflammasome drives inflammation in ischemia\/reperfusion injury after transient middle cerebral artery occlusion in mice","volume":"92","author":"Franke","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s10571-015-0288-1","article-title":"A polymorphism within the 3\u2019UTR of NLRP3 is associated with susceptibility for ischemic stroke in Chinese population","volume":"36","author":"Zhu","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00011-016-0981-7","article-title":"NLRP3 inflammasome: A promising target in ischemic stroke","volume":"66","author":"Gao","year":"2017","journal-title":"Inflamm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13073-021-00863-5","article-title":"Microglial PGC-1\u03b1 protects against ischemic brain injury by suppressing neuroinflammation","volume":"13","author":"Han","year":"2021","journal-title":"Genome Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1007\/s12035-014-8725-6","article-title":"Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke","volume":"51","author":"Jiang","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/cns.12178","article-title":"Nicorandil inhibits inflammasome activation and Toll-like receptor-4 signal transduction to protect against oxygen-glucose deprivation-induced inflammation in BV-2 cells","volume":"20","author":"Zhao","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41586-020-2071-9","article-title":"Gasdermin E suppresses tumour growth by activating anti-tumour immunity","volume":"579","author":"Zhang","year":"2020","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.pneurobio.2013.11.005","article-title":"Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance","volume":"114","author":"Stetler","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1007\/s13311-016-0465-z","article-title":"Neuroimmune response in ischemic preconditioning","volume":"13","author":"McDonough","year":"2016","journal-title":"Neurotherapeutics"},{"key":"ref_21","first-page":"633","article-title":"Ischemic preconditioning reduces ischemic brain injury by suppressing nuclear factor kappa B expression and neuronal apoptosis","volume":"8","author":"Shi","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Liang, J., Luan, Y., Lu, B., Zhang, H., Luo, Y., and Ge, P. (2014). Protection of ischemic postconditioning against neuronal apoptosis induced by transient focal ischemia is associated with attenuation of NF-\u03baB\/p65 activation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096734"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s12975-010-0033-5","article-title":"Toll-like receptor tolerance as a mechanism for neuroprotection","volume":"1","author":"Vartanian","year":"2010","journal-title":"Transl. Stroke Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12974-015-0301-0","article-title":"Function and mechanism of toll-like receptors in cerebral ischemic tolerance: From preconditioning to treatment","volume":"12","author":"Wang","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3389\/fnagi.2020.00054","article-title":"Hypoxia-inducible factor 1\u03b1 and 2\u03b1 have beneficial effects in remote ischemic preconditioning against stroke by modulating inflammatory responses in aged rats","volume":"12","author":"Du","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41419-021-04379-z","article-title":"NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in vitro and protects blood-brain barrier integrity in murine stroke","volume":"13","author":"Bellut","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1111\/cns.13837","article-title":"Fine particulate matter exposure aggravates ischemic injury via NLRP3 inflammasome activation and pyroptosis","volume":"28","author":"Gao","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zuurbier, C.J., Jong, W.M.C., Eerbeek, O., Koeman, A., Pulskens, W.P., Butter, L.M., Leemans, J.C., and Hollmann, M.W. (2012). Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6\/STAT3 signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040643"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s00395-021-00852-0","article-title":"Does remote ischaemic conditioning reduce inflammation? A focus on innate immunity and cytokine response","volume":"116","author":"Pearce","year":"2021","journal-title":"Basic Res. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"395","DOI":"10.4103\/1673-5374.314317","article-title":"Hypoxic preconditioning reduces NLRP3 inflammasome expression and protects against cerebral ischemia\/reperfusion injury","volume":"17","author":"Pang","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12563","DOI":"10.1111\/cpr.12563","article-title":"Role of pyroptosis in cardiovascular disease","volume":"52","author":"Zhaolin","year":"2019","journal-title":"Cell Prolif."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s12975-018-0666-3","article-title":"Gasdermin family: A promising therapeutic target for stroke","volume":"9","author":"Chen","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"717644","DOI":"10.3389\/fnagi.2021.717644","article-title":"Enriched environment attenuates pyroptosis to improve functional recovery after cerebral ischemia\/reperfusion injury","volume":"13","author":"Liu","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s13105-021-00817-w","article-title":"Pyroptosis in stroke-new insights into disease mechanisms and therapeutic strategies","volume":"77","author":"Gou","year":"2021","journal-title":"J. Physiol. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1111\/cns.13384","article-title":"Caspase-1 inhibition prevents neuronal death by targeting the canonical inflammasome pathway of pyroptosis in a murine model of cerebral ischemia","volume":"26","author":"Li","year":"2020","journal-title":"CNS Neurosci. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11234","DOI":"10.18632\/aging.202807","article-title":"Ischemic-hypoxic preconditioning enhances the mitochondrial function recovery of transplanted olfactory mucosa mesenchymal stem cells via miR-181a signaling in ischemic stroke","volume":"13","author":"Zhuo","year":"2021","journal-title":"Aging"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/6\/897\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:47:05Z","timestamp":1760125625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/13\/6\/897"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["brainsci13060897"],"URL":"https:\/\/doi.org\/10.3390\/brainsci13060897","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,1]]}}}