The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia

Author(s): Bruno Costa Silva, Aline Silva de Miranda, Flavia Guimaraes Rodrigues, Ana Leticia Malheiros Silveira, Gustavo Henrique de Souza Resende, Marcio Flavio Dutra Moraes, Antonio Carlos Pinheiro de Oliveira, Patricia Martins Parreiras, Luciola da Silva Barcelos, Mauro Martins Teixeira, Fabiana Simao Machado, Antonio Lucio Teixeira, Milene Alvarenga Rachid.

Journal Name: Current Neurovascular Research

Volume 12 , Issue 4 , 2015

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.

Keywords: Brain, Ischemia, Reperfusion, Inflammation, Zileuton, Mice.

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Article Details

VOLUME: 12
ISSUE: 4
Year: 2015
Page: [398 - 403]
Pages: 6
DOI: 10.2174/1567202612666150812150606
Price: $58

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