The 5-lipoxygenase (5-LOX) inhibitor zileuton reduces inflammation and infarct size with improvement in neurological outcome following cerebral ischemia

Bruno Costa Silva, Aline Silva De Miranda, Flávia Guimarães Rodrigues, Ana Letícia Malheiros Silveira, Gustavo Henrique De Souza Resende, Márcio Flávio Dutra Moraes, Antônio Carlos Pinheiro De Oliveira, Patrícia Martins Parreiras, Lucíola Da Silva Barcelos, Mauro Martins Teixeira, Fabiana Simão Machado, Antônio Lúcio Teixeira, Milene Alvarenga Rachid

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Stroke is one of the most frequent causes of death and disability worldwide causing a major clinical and socioeconomic impact. Although the pathophysiology of brain ischemia and reperfusion is complex, the inflammatory process plays an important role in pathogenesis, contributing to the expansion of brain injury. The 5-lipoxygenase (5-LOX) is a key enzyme in the biosynthesis of the leukotrienes and has been implicated and in the central nervous system (CNS) disorders such as Alzheimer's disease and acute ischemic stroke. Zileuton, a selective 5-LOX inhibitor, has antiinflammatory properties and exerts an inhibitory effect on inflammatory diseases. The objective of this study was to evaluate the effects of blocking 5-LOX activity in a murine model of transient and global brain ischemia. Zileuton improved neurological deficits and significantly decrease volume and density of lesion, compared to vehicle-ischemic animals measured by magnetic resonance imaging (MRI). In addition, the blockage of 5-LOX reduced infarct area and histopathological changes. Furthermore, by enzyme immunoassay (ELISA) increased brain levels of tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C-C motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5) were detected in the vehicle-ischemic group, whereas in Zileuton-ischemic group presented reduction of these mediators. The concentration of the antiinflammatory cytokine interleukin-10 (IL-10) was increased after 5-LOX inhibition. Our results suggest that Zileuton decreases brain damage and reduces inflammatory cytokines expression in the CNS which contributes, at least in part, to improve the neurological outcome of brain ischemia.

Original languageEnglish (US)
Pages (from-to)398-403
Number of pages6
JournalCurrent Neurovascular Research
Volume12
Issue number4
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Keywords

  • Brain
  • Inflammation
  • Ischemia
  • Mice
  • Reperfusion
  • Zileuton

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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