A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats.
In view of a cytoprotective effect of elastase inhibitor on chemokine-mediated tissue injury, we examined the neuroprotective effect of ONO-5046, a specific inhibitor of neutrophil elastase, in rats with spinal cord injury. Standardized spinal cord compression markedly increased cytokine-induced neutrophil chemo-attractant (CINC)-1 mRNA and protein. Their increases correlated with neurologic severity of injured rats. Immunohistochemically, CINC-1 protein was detected sequentially in vascular endothelial cells at 4 h, in perivascular neutrophils at 8 h, and in neutrophils infiltrating into cord substance at 12 h. Pretreatment with ONO-5046 (50 mg/kg) markedly ameliorated motor disturbance in injured rats, and reduced CINC-1 protein and mRNA expression. ONO-5046 also significantly reduced the increase of neutrophil accumulation or infiltration estimated by myeloperoxidase activity, and the extent of vascular permeability by Evans blue extravasation in the injured cord segment in comparison to control animals receiving vehicle. These results suggest that CINC-1 contributed to inflammation in rat spinal cord injury and ONO-5046 attenuated neurologic damage partly by blocking CINC-1 production of the chemoattractant, preventing neutrophil activation and vascular endothelial cell injury.
Tonai
T
T
Department of Orthopedic Surgery and Clinical Research Institute, National Zentsuji Hospital, Kagawa, Japan. ttonai@zentuuji.hosp.go.jp
Shiba
K
K
Taketani
Y
Y
Ohmoto
Y
Y
Murata
K
K
Muraguchi
M
M
Ohsaki
H
H
Takeda
E
E
Nishisho
T
T
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006133:Growth Substances / Q000032:analysis / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000276:immunology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013116:Spinal Cord / Q000201:enzymology / Q000276:immunology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D009195:Peroxidase; D019272:Leukocyte Elastase; D005998:Glycine