Effects of zileuton and montelukast in mouse experimental spinal cord injury.
OBJECTIVE
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).


METHODS
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.


RESULTS
SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis-alpha (TNF-alpha) 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-alpha, 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
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.
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
T
T
Genovese
A
A
Rossi
E
E
Mazzon
R
R
Di Paola
C
C
Muià
R
R
Caminiti
P
P
Bramanti
L
L
Sautebin
S
S
Cuzzocrea
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes; D003545:Cysteine / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000085:Acetates; D003521:Cyclopropanes; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D003545:Cysteine; C093875:montelukast; C063449:zileuton; D006918:Hydroxyurea