{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T05:40:40Z","timestamp":1774935640794,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T00:00:00Z","timestamp":1618876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"McDonnell Center for Cellular and Molecular Neurobiology grant","award":["26275I"],"award-info":[{"award-number":["26275I"]}]},{"DOI":"10.13039\/100013490","name":"Brain Aneurysm Foundation","doi-asserted-by":"publisher","award":["17822"],"award-info":[{"award-number":["17822"]}],"id":[{"id":"10.13039\/100013490","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg\/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.<\/jats:p>","DOI":"10.3390\/ijms22084291","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T13:58:04Z","timestamp":1618927084000},"page":"4291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of SIRT1 in Isoflurane Conditioning-Induced Neurovascular Protection against Delayed Cerebral Ischemia Secondary to Subarachnoid Hemorrhage"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-3384","authenticated-orcid":false,"given":"Meizi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keshav","family":"Jayaraman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1682-2300","authenticated-orcid":false,"given":"Tusar","family":"Giri","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Zipfel","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Washington University in Saint Louis, Saint Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9086-0607","authenticated-orcid":false,"given":"Umeshkumar","family":"Athiraman","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1161\/01.STR.25.7.1342","article-title":"Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage","volume":"25","author":"Broderick","year":"1994","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s12975-013-0316-8","article-title":"Current Management of Delayed Cerebral Ischemia: Update from Results of Recent Clinical Trials","volume":"5","author":"Brathwaite","year":"2014","journal-title":"Transl. Stroke Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S0140-6736(07)60153-6","article-title":"Subarachnoid haemorrhage","volume":"369","author":"Kerr","year":"2007","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1227\/00006123-198805000-00003","article-title":"Altered Cerebral Autoregulation and CO2 Reactivity after Aneurysmal Subarachnoid Hemorrhage","volume":"22","author":"Dernbach","year":"1988","journal-title":"Neurosurgery"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0090-3019(94)90251-8","article-title":"Disturbance of autoregulation in patients with ruptured intracranial aneurysms: Mechanism of cortical and motor dysfunction","volume":"42","author":"Touho","year":"1994","journal-title":"Surg. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neuroscience.2012.08.002","article-title":"Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage","volume":"224","author":"Sabri","year":"2012","journal-title":"Neuroscience"},{"key":"ref_7","first-page":"1761","article-title":"Microthrombosis after Aneurysmal Subarachnoid Hemorrhage: An Additional Explanation for Delayed Cerebral Ischemia","volume":"28","author":"Vergouwen","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/glia.20204","article-title":"Neuroprotective role of astrocytes in cerebral ischemia: Focus on ischemic preconditioning","volume":"50","author":"Trendelenburg","year":"2005","journal-title":"Glia"},{"key":"ref_10","first-page":"399","article-title":"Delayed Cerebrovascular Protective Effect of Lipopolysaccharide in Parallel to Brain Ischemic Tolerance","volume":"23","author":"Bastide","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/s11055-005-0095-0","article-title":"Ischemic Preconditioning of the Rat Brain as a Method of Endothelial Protection from Ischemic\/Repercussion Injury","volume":"35","author":"Vlasov","year":"2005","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_12","first-page":"22","article-title":"Attenuation of Ischemic Brain EDEMA and Cerebrovascular Injury after Ischemic Preconditioning in the Rat","volume":"21","author":"Masada","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1002\/ana.22367","article-title":"Repetitive hypoxia extends endogenous neurovascular protection for stroke","volume":"69","author":"Stowe","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/acn3.170","article-title":"HIF-1\u03b1 Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage","volume":"2","author":"Milner","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e017477","DOI":"10.1161\/JAHA.120.017477","article-title":"Role of Endothelial Nitric Oxide Synthase in Isoflurane Conditioning-Induced Neurovascular Protection in Subarachnoid Hemorrhage","volume":"9","author":"Athiraman","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9989","DOI":"10.1523\/JNEUROSCI.3257-08.2008","article-title":"Brain SIRT1: Anatomical Distribution and Regulation by Energy Availability","volume":"28","author":"Ramadori","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.neuron.2014.01.028","article-title":"SIRT1 in Neurodevelopment and Brain Senescence","volume":"81","author":"Herskovits","year":"2014","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.neuroscience.2008.04.065","article-title":"Modulation of SIRT1 expression in different neurodegenerative models and human pathologies","volume":"154","author":"Pizarro","year":"2008","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s10571-009-9414-2","article-title":"Sirt1\u2032s Complex Roles in Neuroprotection","volume":"29","author":"Tang","year":"2009","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.pneurobio.2011.09.001","article-title":"Protective effects and mechanisms of sirtuins in the nervous system","volume":"95","author":"Zhang","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/neuros\/nyy201","article-title":"SIRT1 Activation: A Potential Strategy for Harnessing Endogenous Protection Against Delayed Cerebral Ischemia After Subarachnoid Hemorrhage","volume":"65","author":"Vellimana","year":"2018","journal-title":"Neurosurgery"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"113484","DOI":"10.1016\/j.expneurol.2020.113484","article-title":"SIRT1 mediates hypoxic preconditioning induced attenuation of neurovascular dysfunction following subarachnoid hemorrhage","volume":"334","author":"Vellimana","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14855","DOI":"10.1073\/pnas.0704329104","article-title":"SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase","volume":"104","author":"Mattagajasingh","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1161\/CIRCRESAHA.108.193102","article-title":"Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1\u03b1 and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes","volume":"104","author":"Rane","year":"2009","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4116","DOI":"10.1128\/MCB.00121-09","article-title":"SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1","volume":"29","author":"Rajamohan","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1111\/j.1600-0625.2010.01129.x","article-title":"Negative regulation of stress-induced matrix metallopro-teinase-9 by Sirt1 in skin tissue","volume":"19","author":"Lee","year":"2010","journal-title":"Exp. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1093\/cvr\/cvq339","article-title":"Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells","volume":"89","author":"Breitenstein","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1478-811X-8-31","article-title":"PARP-1 cleavage fragments: Signatures of cell-death proteases in neurodegeneration","volume":"8","author":"Chaitanya","year":"2010","journal-title":"Cell Commun. Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1161\/STROKEAHA.110.607200","article-title":"Endothelial Nitric Oxide Synthase Mediates Endogenous Protection Against Subarachnoid Hemorrhage-Induced Cerebral Vasospasm","volume":"42","author":"Vellimana","year":"2011","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"156","DOI":"10.2174\/157489008786263989","article-title":"A Review of Sirt1 and Sirt1 Modulators in Cardiovascular and Metabolic Diseases","volume":"3","author":"Pillarisetti","year":"2008","journal-title":"Recent Pat. Cardiovasc. Drug Discov."},{"key":"ref_31","first-page":"125","article-title":"The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity","volume":"206","author":"Satoh","year":"2011","journal-title":"Organotypic Models Drug Dev."},{"key":"ref_32","first-page":"1141","article-title":"Resveratrol Mimics Ischemic Preconditioning in the Brain","volume":"26","author":"Raval","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.4103\/2394-8108.162532","article-title":"Sirt1 in cerebral ischemia","volume":"1","author":"Koronowski","year":"2015","journal-title":"Brain Circ."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2416","DOI":"10.1038\/cddis.2016.292","article-title":"Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats","volume":"7","author":"Zhang","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9627","DOI":"10.3892\/mmr.2017.7773","article-title":"SIRT1 activation by resveratrol reduces brain edema and neuronal apoptosis in an experimental rat subarachnoid hemorrhage model","volume":"16","author":"Qian","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1515\/hsz-2018-0269","article-title":"Resveratrol alleviates early brain injury following subarachnoid hemorrhage: Possible involvement of the AMPK\/SIRT1\/autophagy signaling pathway","volume":"399","author":"Li","year":"2018","journal-title":"Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3171\/2019.3.JNS183512","article-title":"Evidence for a conditioning effect of inhalational anesthetics on angiographic vasospasm after aneurysmal subarachnoid hemorrhage","volume":"133","author":"Athiraman","year":"2020","journal-title":"J. Neurosurg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/neuros\/nyaa356","article-title":"Conditioning Effect of Inhalational Anesthetics on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage","volume":"88","author":"Athiraman","year":"2020","journal-title":"Neurosurgery"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"147169","DOI":"10.1016\/j.brainres.2020.147169","article-title":"Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage","volume":"1750","author":"Athiraman","year":"2021","journal-title":"Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.wneu.2020.08.198","article-title":"Anesthetic Conditioning for Secondary Brain Injury After Aneurysmal Subarachnoid Hemorrhage","volume":"143","author":"Athiraman","year":"2020","journal-title":"World Neurosurg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1152\/japplphysiol.00780.2014","article-title":"Hypoxia-inducible factor-1 modulates the expression of vascular endothelial growth factor and endothelial nitric oxide synthase induced by eccentric exercise","volume":"118","author":"Almar","year":"2015","journal-title":"J. Appl. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Alique, M., S\u00e1nchez-L\u00f3pez, E., Bodega, G., Giannarelli, C., Carracedo, J., and Ram\u00edrez, R. (2020). Hypoxia-Inducible Factor-1\u03b1: The Master Regulator of Endothelial Cell Senescence in Vascular Aging. Cells, 9.","DOI":"10.3390\/cells9010195"},{"key":"ref_43","first-page":"132","article-title":"Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats","volume":"31","author":"Nagel","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/cns.13042","article-title":"DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic\/high-glucose conditions, potentially through the SIRT1\/HIF-1\/VEGF pathway","volume":"25","author":"Mi","year":"2018","journal-title":"CNS Neurosci. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.physbeh.2018.07.017","article-title":"Sirt1 mediates improvement of isoflurane-induced memory impairment following hyperbaric oxygen preconditioning in middle-aged mice","volume":"195","author":"Fen","year":"2018","journal-title":"Physiol. Behav."},{"key":"ref_46","first-page":"4288","article-title":"Chikusetsu saponin IVa attenuates isoflurane-induced neurotoxicity and cognitive def-icits via SIRT1\/ERK1\/2 in developmental rats","volume":"9","author":"Fang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/mmr.2020.11662","article-title":"AMPK-SIRT1 pathway dysfunction contributes to neuron apoptosis and cognitive impairment induced by sevoflurane","volume":"23","author":"Liu","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1007\/s12031-020-01612-w","article-title":"AMPK-SIRT1-PGC1\u03b1 Signal Pathway Influences the Cognitive Function of Aged Rats in Sevoflurane-Induced Anesthesia","volume":"70","author":"Yang","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1158\/1535-7163.MCT-09-0971","article-title":"SIRT Inhibitors Induce Cell Death and p53 Acetylation through Targeting Both SIRT1 and SIRT2","volume":"9","author":"Peck","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-09070-y","article-title":"A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage","volume":"7","author":"Aum","year":"2017","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:50:25Z","timestamp":1760161825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,20]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22084291"],"URL":"https:\/\/doi.org\/10.3390\/ijms22084291","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,20]]}}}