Effects of zileuton and montelukast in mouse experimental spinal cord injury

T. Genovese, A. Rossi, E. Mazzon, R. Di Paola, C. Muià, R. Caminiti, P. Bramanti, L. Sautebin, S. Cuzzocrea

Research output: Contribution to journalArticlepeer-review

Abstract

Background and purpose: 5-lipoxygenase (5-LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5-LO-product, cysteinyl-LT (Cys-LT), with a 5-LO inhibitor (zileuton) and a Cys-LT, receptor antagonist (montelukast), in the inflammatory response and tissue injury associated with spinal cord injury (SCI). Experimental approach: SCI was induced in mice by the application of vascular clips to the dura via a two-level T6 to T7 laminectomy for 1 min. Cord inflammation was assessed histologically and by measuring inflammatory mediators (ELISA) and apoptosis by annexin V, TUNEL, Fas ligand staining and Bax and Bcl-2 expression (immunohistochemistry and western blots). Motor function in hindlimbs was assessed by a locomotor rating scale, for 10 days after cord injury. Key results: SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis-α (TNF-α) and cyclooxygenase-2 (COX-2) expression, prostaglandin E 2 (PGE 2) and leukotriene B 4 (LTB 4) production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in injured tissue. Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury, neutrophil infiltration, TNF-α, COX-2 and pERK1/2 expression, PGE 2 and LTB 4 production, and apoptosis. In separate experiments, zileuton or montelukast significantly improved the recovery of limb function over 10 days. Conclusions and implications: Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI. Our data underline the important role of 5-LO and Cys-LT in neurotrauma.

Original languageEnglish
Pages (from-to)568-582
Number of pages15
JournalBritish Journal of Pharmacology
Volume153
Issue number3
DOIs
Publication statusPublished - Feb 2008

Keywords

  • 5-lipoxygenase
  • Cysteinyl- leukotrienes
  • Montelukast
  • Spinal cord injury
  • Zileuton

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Effects of zileuton and montelukast in mouse experimental spinal cord injury'. Together they form a unique fingerprint.

Cite this