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

Dienel, Ari; Hong, Sung Ha; Zeineddine, Hussein A; Thomas, Sithara; Shafeeque, C M; Jose, Dania A; Torres, Kiara; Guzman, Jose; Dunn, Andrew; P Kumar, T; Rao, Gadiparthi N; Blackburn, Spiros L; McBride, Devin W

Dienel, Ari; Hong, Sung Ha; Zeineddine, Hussein A; Thomas, Sithara; Shafeeque, C M; Jose, Dania A; Torres, Kiara; Guzman, Jose; Dunn, Andrew; P Kumar, T; Rao, Gadiparthi N; Blackburn, Spiros L; McBride, Devin W.

Afiliação

Dienel A; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Hong SH; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Zeineddine HA; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Thomas S; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Shafeeque CM; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Jose DA; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Torres K; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Guzman J; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Dunn A; The University of Texas at Austin.
P Kumar T; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
Rao GN; University of Tennessee Health Science Center.
Blackburn SL; The Vivian L. Smith, The University of Texas Health Science Center at Houston.
McBride DW; The Vivian L. Smith, The University of Texas Health Science Center at Houston.

Res Sq ; 2024 Jun 12.

Article em En | MEDLINE | ID: mdl-38947083

ABSTRACT

ABSTRACT

Background and

Purpose:

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.

Methods:

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 five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for 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.

Results:

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.

Conclusions:

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.

Palavras-chave

12/15-Lipooxygenase; arterioles; delayed neurological deficit; microthrombi; microvessel constrictions; platelets; subarachnoid hemorrhage

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