{"doi":"10.1007/s12975-024-01295-0","title":"12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi After Subarachnoid Hemorrhage in Mice","abstract":"Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX −/− mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day 5 to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. In SAH mice, 12/15-LOX was upregulated in brain vascular cells, and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4–5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.","journal":"Translational Stroke Research","year":2024,"id":449235,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1268566,"name":"Sung‐Ha Hong","orcid":"0000-0003-4529-2257","position":1,"is_corresponding":false},{"id":505140,"name":"Hussein A. Zeineddine","orcid":"0000-0001-6144-8392","position":2,"is_corresponding":false},{"id":683398,"name":"Sithara Thomas","orcid":"0000-0003-4458-4426","position":3,"is_corresponding":false},{"id":1268567,"name":"Chathathayil Mohammedali Shafeeque","orcid":"0000-0003-2795-8086","position":4,"is_corresponding":false},{"id":1012135,"name":"Dania Jose","orcid":null,"position":5,"is_corresponding":false},{"id":1156473,"name":"Kiara Torres","orcid":null,"position":6,"is_corresponding":false},{"id":944049,"name":"José Ignacio Navarro Guzmán","orcid":"0000-0002-0738-2641","position":7,"is_corresponding":false},{"id":288013,"name":"Andrew K. Dunn","orcid":"0000-0001-6500-5783","position":8,"is_corresponding":false},{"id":481938,"name":"Peeyush Kumar T.","orcid":null,"position":9,"is_corresponding":false},{"id":241667,"name":"Gadiparthi N. Rao","orcid":"0000-0002-9922-5829","position":10,"is_corresponding":false},{"id":479486,"name":"Spiros Blackburn","orcid":"0000-0003-2902-5079","position":11,"is_corresponding":false},{"id":459289,"name":"Devin W. McBride","orcid":"0000-0001-8988-3353","position":12,"is_corresponding":false},{"id":480872,"name":"Ari Dienel","orcid":"0000-0003-4825-5005","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:02:16.291892Z","pmid":"39294532","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}