Neuroprotective synergy of N-methyl-D-aspartate receptor antagonist (MK801) and protein synthesis inhibitor (cycloheximide) on spinal cord ischemia-reperfusion injury in rats.
Thoraco-abdominal aortic surgery requiring temporal cross clamping of the aorta results in a high incidence of paraplegia due to temporary ischemia of the spinal cord. Both excitotoxicity and apoptosis are implicated in the pathogenesis of spinal cord ischemia-reperfusion injury. We propose that the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (MK801) and the protein synthesis inhibitor cycloheximide produce a synergic effect in a rodent model of spinal cord ischemia-reperfusion injury. Injury was induced by 20 min of temporal thoracic aorta occlusion and distal blood volume reduction. After injury, the animals were treated with vehicle, MK801, cycloheximide or MK801 and cycloheximide. Hind limb motor function recovery was better in the MK801 and combined therapy groups than in the control and cycloheximide groups. The mean neuronal survival rate of the control group was 45.3 +/- 3.2% on the 7(th) day after injury. In the MK801 and cycloheximide treatment groups, neuronal survival increased to 62.4 +/- 3.6% and 54.1 +/- 2.4%, respectively. For the combined therapy group, neuronal survival increased to 75.6 +/- 2.5%. The number of apoptotic cells in the control group was 211.4 +/- 8.8 per section on the 7th day after ischemic insult, while apoptosis was significantly reduced in the cycloheximide (96.8 +/- 6.7 cells) and combined (84.8 +/- 8.5 cells) groups. It was unchanged in the MK801 group (209.8 +/- 5.4 cells). These results suggest that combined treatments directed at blocking both N-methyl-D-aspartate receptor-mediated excitotoxic necrosis and caspase-mediated apoptosis might have synergic therapeutic potential in reducing spinal cord ischemia-reperfusion injury.
Liang
Cheng-Loong
CL
Department of Neurosurgery, Chang Gung Memorial Hospital, Kaohsiung Medical Centre, Kaohsiung, Taiwan.
Yang
Lin-Cheng
LC
Lu
Kang
K
Hsu
Huan-Chen
HC
Cho
Chung-Lung
CL
Chen
Shang-Der
SD
Huang
Hsuan-Ying
HY
Chen
Han-Jung
HJ
D000818:Animals; D017209:Apoptosis; D003513:Cycloheximide / Q000627:therapeutic use*; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D008297:Male; D009336:Necrosis; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011500:Protein Synthesis Inhibitors; D016291:Dizocilpine Maleate; D003513:Cycloheximide