ONO-5046 attenuation of delayed motor neuron death and effect on the induction of brain-derived neurotrophic factor, phosphorylated extracellular signal-regulated kinase, and caspase3 after spinal cord ischemia in rabbits.
OBJECTIVE
The mechanism of spinal cord injury is believed to be related to the vulnerability of spinal motor neuron cells to ischemia. The aim of this study was to investigate whether ONO-5046, a specific inhibitor of neutrophil elastase that can attenuate tissue or organ injury in various pathologic conditions, could protect against ischemic spinal cord damage.


METHODS
After induction of spinal ischemia, ONO-5046 or vehicle was injected intravenously. Cell damage was analyzed by counting the number of motor neurons. To investigate the mechanism by which ONO-5046 prevents ischemic spinal cord damage, we observed the immunoreactivity of CPP32 (caspase3), brain-derived neurotrophic factor, and phosphorylated extracellular signal-regulated kinase.


RESULTS
ONO-5046 eased the functional deficits and increased the number of motor neurons after ischemia. The induction of caspase3 was significantly reduced by ONO-5046 treatment. Furthermore, the expressions of brain-derived neurotrophic factor and phosphorylated extracellular signal-regulated kinase were prolonged.


CONCLUSIONS
ONO-5046 may protect motor neurons from ischemic injury by reducing caspase3 and prolonging the expressions of brain-derived neurotrophic factor and phosphorylated extracellular signal-regulated kinase. ONO-5046 may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury.
Yamauchi
Takashi
T
Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Sawa
Yoshiki
Y
Sakurai
Masahiro
M
Hiroshi
Takano
T
Matsumiya
Goro
G
Abe
Koji
K
Matsuda
Hikaru
H
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects*; D010766:Phosphorylation; D011817:Rabbits; D020760:Spinal Cord Ischemia / Q000517:prevention & control*; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D013449:Sulfonamides; C069195:sivelestat; D048049:Extracellular Signal-Regulated MAP Kinases; D019272:Leukocyte Elastase; D053148:Caspase 3; D020169:Caspases; D005998:Glycine