{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:29:00Z","timestamp":1782876540625,"version":"3.54.5"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007792","name":"Society of Critical Care Medicine","doi-asserted-by":"publisher","award":["Weill Research Grant 2022"],"award-info":[{"award-number":["Weill Research Grant 2022"]}],"id":[{"id":"10.13039\/100007792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017460","name":"Brain Institute, University of Virginia","doi-asserted-by":"publisher","award":["Pilot grant 2023"],"award-info":[{"award-number":["Pilot grant 2023"]}],"id":[{"id":"10.13039\/100017460","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurocrit Care"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Delayed cerebral injury (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is a preventable injury that would improve patient outcomes if an effective treatment can be developed. The most common long-term disability in patients with SAH is cognitive dysfunction. Contrary to the common theory that damage from DCI originates solely from ischemia caused by cerebral vasospasm, inflammation has been shown to be an important independent mediator of DCI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Neutrophil infiltration of the meninges is a critical step in developing late spatial memory deficits in a murine model of SAH and may serve as a surrogate marker for disease progression. Importantly, myeloperoxidase (\n                      <jats:italic>MPO<\/jats:italic>\n                      ) null mice do not develop meningeal neutrophilia and are protected from spatial memory deficits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this study, wildtype mice administered a single dose of the MPO inhibitor (MPOi) AZD5904 at peak neutrophil entry day have a higher percentage of neutrophils that remain in the meningeal blood vessel 6\u00a0days after the hemorrhage suggesting neutrophil extravasation into the meninges is inhibited (79\u2009\u00b1\u200920 vs. 28\u2009\u00b1\u200924,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Interestingly, the intraperitoneal route of administration has a larger effect than the intrathecal route suggesting that MPO inhibition is best administered systemically not in the central nervous system. Second, mice administered AZD5904 intraperitoneal for 4 consecutive days starting 2\u00a0days after the hemorrhage do not develop delayed spatial memory dysfunction (two-way analysis of variance,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&gt;\u20090.001\n                      <jats:italic>F<\/jats:italic>\n                      [2, 22]\u2009=\u200910.11).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Systemic MPOi prevents neutrophil entry into the meninges and prevents spatial memory dysfunction. MPOi is a promising strategy for translation to patients with aneurysmal SAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12028-024-02169-x","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T19:29:11Z","timestamp":1733772551000},"page":"945-952","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Small Molecule Myeloperoxidase (MPO) Inhibition Prevents Delayed Cerebral Injury (DCI) After Subarachnoid Hemorrhage (SAH) in a Murine Model"],"prefix":"10.1007","volume":"42","author":[{"given":"Safiye","family":"Limon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aminata P.","family":"Coulibaly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-1806","authenticated-orcid":false,"given":"Jose Javier","family":"Provencio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"issue":"Pt 2","key":"2169_CR1","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1093\/brain\/124.2.249","volume":"124","author":"J van Gijn","year":"2001","unstructured":"van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain. 2001;124(Pt 2):249\u201378. https:\/\/doi.org\/10.1093\/brain\/124.2.249.","journal-title":"Brain"},{"issue":"1","key":"2169_CR2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s12028-019-00905-2","volume":"33","author":"M Seule","year":"2020","unstructured":"Seule M, Oswald D, Muroi C, Brandi G, Keller E. Outcome, Return to Work and Health-Related Costs After Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2020;33(1):49\u201357. https:\/\/doi.org\/10.1007\/s12028-019-00905-2.","journal-title":"Neurocrit Care"},{"key":"2169_CR3","doi-asserted-by":"publisher","unstructured":"Sorteberg A, Lashkarivand, A, Western, E. Return to work after aneurysmal subarachnoid hemorrhage. Frontiers in Neurology 2024;15:Stroke:1401493. https:\/\/doi.org\/10.3389\/fneur.2024.1401493.","DOI":"10.3389\/fneur.2024.1401493"},{"key":"2169_CR4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1478-7547-8-6","volume":"8","author":"O Rivero-Arias","year":"2010","unstructured":"Rivero-Arias O, Gray A, Wolstenholme J. Burden of disease and costs of aneurysmal subarachnoid haemorrhage (aSAH) in the United Kingdom. Cost Eff Resour Alloc. 2010;8:6. https:\/\/doi.org\/10.1186\/1478-7547-8-6.","journal-title":"Cost Eff Resour Alloc"},{"issue":"8","key":"2169_CR5","doi-asserted-by":"publisher","first-page":"e519","DOI":"10.1161\/STROKEAHA.110.581975","volume":"41","author":"T Al-Khindi","year":"2010","unstructured":"Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41(8):e519\u201336. https:\/\/doi.org\/10.1161\/STROKEAHA.110.581975.","journal-title":"Stroke"},{"key":"2169_CR6","doi-asserted-by":"publisher","unstructured":"Haley EC, Jr., Kassell NF, Torner JC. A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results. A report of the Cooperative Aneurysm Study. J Neurosurg 1993;78(4):548\u201353. https:\/\/doi.org\/10.3171\/jns.1993.78.4.0548.","DOI":"10.3171\/jns.1993.78.4.0548"},{"key":"2169_CR7","doi-asserted-by":"publisher","unstructured":"Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P. Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine. Acta Neurochir (Wien) 1986;82(3\u20134):110\u20134. https:\/\/doi.org\/10.1007\/BF01456369.","DOI":"10.1007\/BF01456369"},{"key":"2169_CR8","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-3-7091-1192-5_7","volume":"115","author":"RL Macdonald","year":"2013","unstructured":"Macdonald RL, Higashida RT, Keller E, et al. Randomised trial of clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid hemorrhage undergoing surgical clipping (CONSCIOUS-2). Acta Neurochir Suppl. 2013;115:27\u201331. https:\/\/doi.org\/10.1007\/978-3-7091-1192-5_7.","journal-title":"Acta Neurochir Suppl"},{"issue":"3","key":"2169_CR9","doi-asserted-by":"publisher","first-page":"E2","DOI":"10.3171\/foc.2006.21.3.2","volume":"21","author":"SC Stein","year":"2006","unstructured":"Stein SC, Levine JM, Nagpal S, LeRoux PD. Vasospasm as the sole cause of cerebral ischemia: how strong is the evidence? Neurosurg Focus. 2006;21(3):E2. https:\/\/doi.org\/10.3171\/foc.2006.21.3.2.","journal-title":"Neurosurg Focus"},{"issue":"11","key":"2169_CR10","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1097\/CCM.0000000000003373","volume":"46","author":"SH Chou","year":"2018","unstructured":"Chou SH. Inflammation, Cerebral Vasospasm, and Brain Injury in Subarachnoid Hemorrhage-A Shifting Paradigm and a New Beginning. Crit Care Med. 2018;46(11):1883\u20135. https:\/\/doi.org\/10.1097\/CCM.0000000000003373.","journal-title":"Crit Care Med"},{"issue":"9","key":"2169_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2021.105936","volume":"30","author":"JJ Chang","year":"2021","unstructured":"Chang JJ, Dowlati E, Triano M, et al. Admission Neutrophil to Lymphocyte Ratio for Predicting Outcome in Subarachnoid Hemorrhage. J Stroke Cerebrovasc Dis. 2021;30(9): 105936. https:\/\/doi.org\/10.1016\/j.jstrokecerebrovasdis.2021.105936.","journal-title":"J Stroke Cerebrovasc Dis"},{"issue":"3","key":"2169_CR12","doi-asserted-by":"publisher","first-page":"E4","DOI":"10.3171\/2021.12.FOCUS21642","volume":"52","author":"WS Bolton","year":"2022","unstructured":"Bolton WS, Gharial PK, Akhunbay-Fudge C, Chumas P, Mathew RK, Anderson IA. Day 2 neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for prediction of delayed cerebral ischemia in subarachnoid hemorrhage. Neurosurg Focus. 2022;52(3):E4. https:\/\/doi.org\/10.3171\/2021.12.FOCUS21642.","journal-title":"Neurosurg Focus"},{"issue":"1\u20132","key":"2169_CR13","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jneuroim.2010.10.016","volume":"232","author":"JJ Provencio","year":"2011","unstructured":"Provencio JJ, Altay T, Smithason S, Moore SK, Ransohoff RM. Depletion of Ly6G\/C(+) cells ameliorates delayed cerebral vasospasm in subarachnoid hemorrhage. J Neuroimmunol. 2011;232(1\u20132):94\u2013100. https:\/\/doi.org\/10.1016\/j.jneuroim.2010.10.016.","journal-title":"J Neuroimmunol"},{"key":"2169_CR14","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.bbi.2016.02.007","volume":"54","author":"JJ Provencio","year":"2016","unstructured":"Provencio JJ, Swank V, Lu H, et al. Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors. Brain Behav Immun. 2016;54:233\u201342. https:\/\/doi.org\/10.1016\/j.bbi.2016.02.007.","journal-title":"Brain Behav Immun"},{"issue":"1","key":"2169_CR15","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s12028-019-00871-9","volume":"33","author":"AP Coulibaly","year":"2020","unstructured":"Coulibaly AP, Gartman WT, Swank V, et al. RAR-related orphan receptor gamma T (RoRgammat)-related cytokines play a role in neutrophil infiltration of the central nervous system after subarachnoid hemorrhage. Neurocrit Care. 2020;33(1):140\u201351. https:\/\/doi.org\/10.1007\/s12028-019-00871-9.","journal-title":"Neurocrit Care"},{"issue":"10","key":"2169_CR16","doi-asserted-by":"publisher","first-page":"3374","DOI":"10.1161\/STROKEAHA.120.033513","volume":"52","author":"AP Coulibaly","year":"2021","unstructured":"Coulibaly AP, Pezuk P, Varghese P, et al. Neutrophil enzyme myeloperoxidase modulates neuronal response in a model of subarachnoid hemorrhage by venous injury. Stroke. 2021;52(10):3374\u201384. https:\/\/doi.org\/10.1161\/STROKEAHA.120.033513.","journal-title":"Stroke"},{"issue":"Pt 9","key":"2169_CR17","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1093\/brain\/awv184","volume":"138","author":"A Jucaite","year":"2015","unstructured":"Jucaite A, Svenningsson P, Rinne JO, et al. Effect of the myeloperoxidase inhibitor AZD3241 on microglia: a PET study in Parkinson\u2019s disease. Brain. 2015;138(Pt 9):2687\u2013700. https:\/\/doi.org\/10.1093\/brain\/awv184.","journal-title":"Brain"},{"issue":"11","key":"2169_CR18","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1002\/jcph.1134","volume":"58","author":"X Tong","year":"2018","unstructured":"Tong X, Zhou D, Savage A, et al. Population pharmacokinetic modeling with enterohepatic circulation for AZD3241 in healthy subjects and patients with multiple system atrophy. J Clin Pharmacol. 2018;58(11):1452\u201360. https:\/\/doi.org\/10.1002\/jcph.1134.","journal-title":"J Clin Pharmacol"},{"issue":"2","key":"2169_CR19","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1007\/s12028-009-9308-7","volume":"12","author":"JJ Provencio","year":"2010","unstructured":"Provencio JJ, Fu X, Siu A, Rasmussen PA, Hazen SL, Ransohoff RM. CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care. 2010;12(2):244\u201351. https:\/\/doi.org\/10.1007\/s12028-009-9308-7.","journal-title":"Neurocrit Care"},{"issue":"2","key":"2169_CR20","doi-asserted-by":"publisher","first-page":"e005837","DOI":"10.1136\/jitc-2022-005837","volume":"11","author":"TW Liu","year":"2023","unstructured":"Liu TW, Gammon ST, Yang P, Ma W, Wang J, Piwnica-Worms D. Inhibition of myeloperoxidase enhances immune checkpoint therapy for melanoma. J Immunother Cancer. 2023;11(2):e005837. https:\/\/doi.org\/10.1136\/jitc-2022-005837.","journal-title":"J Immunother Cancer"},{"issue":"11","key":"2169_CR21","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1039\/c7md00268h","volume":"8","author":"F Duclos","year":"2017","unstructured":"Duclos F, Abell LM, Harden DG, et al. Triazolopyrimidines identified as reversible myeloperoxidase inhibitors. Medchemcomm. 2017;8(11):2093\u20139. https:\/\/doi.org\/10.1039\/c7md00268h.","journal-title":"Medchemcomm"},{"issue":"2","key":"2169_CR22","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.jneumeth.2009.06.027","volume":"183","author":"T Altay","year":"2009","unstructured":"Altay T, Smithason S, Volokh N, Rasmussen PA, Ransohoff RM, Provencio JJ. A novel method for subarachnoid hemorrhage to induce vasospasm in mice. J Neurosci Methods. 2009;183(2):136\u201340. https:\/\/doi.org\/10.1016\/j.jneumeth.2009.06.027.","journal-title":"J Neurosci Methods"},{"issue":"4","key":"2169_CR23","first-page":"387","volume":"87","author":"DA Sholl","year":"1953","unstructured":"Sholl DA. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 1953;87(4):387\u2013406.","journal-title":"J Anat"},{"issue":"8","key":"2169_CR24","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1136\/jnnp.2002.000414","volume":"75","author":"J Powell","year":"2004","unstructured":"Powell J, Kitchen N, Heslin J, Greenwood R. Psychosocial outcomes at 18 months after good neurological recovery from aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2004;75(8):1119\u201324. https:\/\/doi.org\/10.1136\/jnnp.2002.000414.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"3","key":"2169_CR25","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1007\/s12028-008-9054-2","volume":"8","author":"R Dhar","year":"2008","unstructured":"Dhar R, Diringer MN. The burden of the systemic inflammatory response predicts vasospasm and outcome after subarachnoid hemorrhage. Neurocrit Care. 2008;8(3):404\u201312. https:\/\/doi.org\/10.1007\/s12028-008-9054-2.","journal-title":"Neurocrit Care"},{"issue":"6","key":"2169_CR26","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1093\/neuros\/nyab354","volume":"89","author":"JR Geraghty","year":"2021","unstructured":"Geraghty JR, Lung TJ, Hirsch Y, et al. Systemic immune-inflammation index predicts delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2021;89(6):1071\u20139. https:\/\/doi.org\/10.1093\/neuros\/nyab354.","journal-title":"Neurosurgery"},{"key":"2169_CR27","doi-asserted-by":"publisher","first-page":"113","DOI":"10.3389\/fphys.2018.00113","volume":"9","author":"C Rosales","year":"2018","unstructured":"Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types? Front Physiol. 2018;9:113. https:\/\/doi.org\/10.3389\/fphys.2018.00113.","journal-title":"Front Physiol"},{"issue":"5420","key":"2169_CR28","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1126\/science.284.5420.1670","volume":"284","author":"JC Crabbe","year":"1999","unstructured":"Crabbe JC, Wahlsten D, Dudek BC. Genetics of mouse behavior: interactions with laboratory environment. Science. 1999;284(5420):1670\u20132. https:\/\/doi.org\/10.1126\/science.284.5420.1670.","journal-title":"Science"},{"issue":"1","key":"2169_CR29","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s40614-019-00193-3","volume":"42","author":"S Laraway","year":"2019","unstructured":"Laraway S, Snycerski S, Pradhan S, Huitema BE. An overview of scientific reproducibility: consideration of relevant issues for behavior science\/analysis. Perspect Behav Sci. 2019;42(1):33\u201357. https:\/\/doi.org\/10.1007\/s40614-019-00193-3.","journal-title":"Perspect Behav Sci"}],"container-title":["Neurocritical Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12028-024-02169-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12028-024-02169-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12028-024-02169-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:27:36Z","timestamp":1749036456000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12028-024-02169-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,10]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["2169"],"URL":"https:\/\/doi.org\/10.1007\/s12028-024-02169-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4595560\/v1","asserted-by":"object"}]},"ISSN":["1541-6933","1556-0961"],"issn-type":[{"value":"1541-6933","type":"print"},{"value":"1556-0961","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,10]]},"assertion":[{"value":"20 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"This study adheres to ethical guidelines for animal use and was approved by the Animal Care and Use Committee at the University of Virginia.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval\/Animal Rights"}},{"value":"Society of Critical Care Medicine Weill Research Grant and University of Virginia Brain Institute Transformative Neuroscience Pilot Grants for Basic Science.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Source of support"}}]}}