Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2008) 153, 568–582; doi:10.1038/sj.bjp.0707577; published online 3 December 2007
Effects of zileuton and montelukast in mouse experimental spinal cord injury
T Genovese1,2,5, A Rossi2,3,5, E Mazzon1,2, R Di Paola1,2, C Muià1, R Caminiti4, P Bramanti2, L Sautebin3 and S Cuzzocrea1,2
- 1Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy
- 2IRCCS Centro Neurolesi 'Bonino-Pulejo', Messina, Italy
- 3Department of Experimental Pharmacology, University of Naples 'Federico II', Naples, Italy
- 4Department of Human Pathology, School of Medicine, University of Messina, Messina, Italy
Correspondence: Professor S Cuzzocrea, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Via C. Valeria, Messina 5-98125, Italy. E-mail: salvator@unime.it
5These authors contributed equally to the present results and share the first authorship.
Received 8 August 2007; Revised 11 September 2007; Accepted 19 September 2007; Published online 3 December 2007.
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-
(TNF-) and cyclooxygenase-2 (COX-2) expression, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) 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-, COX-2 and pERK1/2 expression, PGE2 and LTB4 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.
Keywords:
zileuton, montelukast, spinal cord injury, 5-lipoxygenase, cysteinyl-leukotrienes
Abbreviations:
COX-2, cyclooxygenase-2; Cys-LT, cysteinyl-LT; ERK1/2, extracellular signal-regulated kinase 1/2; 5-LO, 5-lipoxygenase; LT, leukotrienes; LTB4, leukotriene B4; LTC4, leukotriene C4; MAPK, mitogen-activated protein kinase; MPO, myeloperoxidase; PG, prostaglandin; SCI, spinal cord injury; TNF-, tumour necrosis factor-alpha
