The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia.
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.
Bruno Costa
BC
Silva
Aline Silva
AS
de Miranda
Flavia Guimaraes
FG
Rodrigues
Ana Leticia Malheiros
AL
Silveira
Gustavo Henrique de Souza
GH
Resende
Marcio Flavio Dutra
MF
Moraes
Antonio Carlos Pinheiro
AC
de Oliveira
Patricia Martins
PM
Parreiras
Luciola da Silva
Lda S
Barcelos
Mauro Martins
MM
Teixeira
Fabiana Simao
FS
Machado
Antonio Lucio
AL
Teixeira
Universidade Federal de Minas Gerais, Instituto de Ciencias Biologicas. Departamento de Patologia Geral. Laboratorio de Apoptose, Campus Pampulha, Av. Antonio Carlos 6.627 - Belo Horizonte, Minas Gerais. Brazil. milenerachid@gmail.com.
Milene Alvarenga
MA
Rachid
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D020520:Brain Infarction / Q000188:drug therapy* / Q000209:etiology; D016893:Carotid Stenosis / Q000150:complications; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D004797:Enzyme-Linked Immunosorbent Assay; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000150:complications* / Q000209:etiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; C063449:zileuton; D006918:Hydroxyurea