12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi After Subarachnoid Hemorrhage in Mice.

Autor: Dienel A; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA. ari.c.dienel@uth.tmc.edu., Hong SH; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Zeineddine HA; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Thomas S; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., M SC; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Jose DA; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Torres K; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Guzman J; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Dunn A; Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA.; Department of Electrical and Computer Engineering, The University of Texas at Austin, Austin, TX, 78712, USA., T PK; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., Rao GN; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA., Blackburn SL; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA., McBride DW; The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77459, USA. devin.w.mcbride@uth.tmc.edu.
Jazyk: angličtina
Zdroj: Translational stroke research [Transl Stroke Res] 2024 Sep 19. Date of Electronic Publication: 2024 Sep 19.
DOI: 10.1007/s12975-024-01295-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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