MCI-186 reduces oxidative cellular damage and increases DNA repair function in the rabbit spinal cord after transient ischemia.
BACKGROUND
Paraplegia is a serious complication of operations on the thoracic and thoracoabdominal aorta. To investigate the mechanism by which motor neurons are damaged during these operations, we have reported a rabbit model of spinal cord ischemia. We also tested whether a free radical scavenger MCI-186 that is useful for treating ischemic damage in the brain can protect against ischemic spinal cord damage.


METHODS
Fifteen minutes of ischemia was induced, then MCI-186 or vehicle was injected intravenously. Cell damage was analyzed by observing the function of the lower limbs and by counting the number of motor neurons. To investigate the mechanism by which MCI-186 prevents ischemic spinal cord damage, we observed the immunoreactivity of 8-hydroxy-2'-deoxyguanosine as an oxidative DNA damage marker and redox effector as a DNA repair marker.


RESULTS
In sham control, 8-hydroxy-2'-deoxyguanosine was not observed, and the nuclear expression of redox effector was observed. In vehicle injection group (group I), the nuclear expression of 8-hydroxy-2'-deoxyguanosine was observed at 1 and 2 days after reperfusion. The nuclear expression of redox effector was observed at 8 hours and 1 day, and disappeared at 2 days after transient ischemia. In MCI-186 injection group (group M), the nuclear expression of 8-hydroxy-2'-deoxyguanosine was not observed, and redox effector was observed at 8 hours and 1 and 2 days.


CONCLUSIONS
These results suggest that redox effector decreased in motor neurons after transient ischemia and this reduction preceded oxidative DNA damage. MCI-186 works as a radical scavenger and reduced oxidative DNA damage, so redox effector did not disappear. MCI-186 could be a strong candidate for a use as a therapeutic agent in the treatment of ischemic spinal cord injury.
Takahashi
Goro
G
Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
Sakurai
Masahiro
M
Abe
Koji
K
Itoyama
Yasuto
Y
Tabayashi
Koichi
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001259:Ataxia / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers; D002452:Cell Count; D002467:Cell Nucleus / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000032:analysis; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D023421:Models, Animal; D009046:Motor Neurons / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000032:analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010264:Paraplegia / Q000209:etiology / Q000517:prevention & control*; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D011817:Rabbits; D013116:Spinal Cord / Q000098:blood supply*
D015415:Biomarkers; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine; D000077553:Edaravone; D000983:Antipyrine