Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation.
Abstract | OBJECTIVE: SUMMARY BACKGROUND DATA: METHODS: In rats, spinal cord ischemia was induced by using a balloon catheter placed into the aorta. After the transient ischemia, survival and motor function were evaluated, and histologic examination of the spinal cord was performed by using both hematoxylin-and- eosin staining and 2,3,5, - triphenyltetrazolium chloride (TTC) staining 24 hours after the ischemia. Tissue levels of myeloperoxidase and cytokines, including tumor necrosis factor-alpha ( TNF-alpha) and rat interleukin-8, were measured in six experimental groups: sham-operated, control, APC (100 microg/kg, intravenous), dansyl glutamyl-glycyl-arginyl chloromethyl ketone-treated activated factor X (DEGR-F.Xa), a selective inhibitor of thrombin generation (1 mg/kg, intravenous), nitrogen mustard-induced leukocytopenia, and diisopropyl fluorophosphate-treated APC (DIP-APC), active site-blocked APC (100 microg/kg, intravenous). APC, DEGR-F.Xa, and DIP-APC were administered intravenously 30 minutes before aortic occlusion. Control and leukocytopenic rats received saline instead of other drugs. RESULTS: Pretreatment with APC significantly reduced motor disturbances compared with those in control animals. In contrast, neither DEGR-F.Xa nor DIP-APC had any effect. Microinfarctions, evidenced by the absence of TTC staining and histologic change, were markedly reduced in animals given APC. The increases in the tissue levels of TNF-alpha, rat interleukin-8, and myeloperoxidase in the ischemic part of the spinal cord were significantly reduced in animals that received APC. These levels were not reduced in rats given DEGR-F.Xa or DIP-APC. Leukocytopenia produced effects similar to those of APC. CONCLUSIONS: APC reduced the ischemia/reperfusion-induced spinal cord injury by inhibiting neutrophil activation. The therapeutic mechanisms of APC might depend on its inhibitory effect on the production of TNF-alpha, which is a potent activator of neutrophils. Although the anticoagulant effects of APC might not be related to its ability to inhibit TNF-alpha production, its serine protease activity appears to be essential in the therapeutic mechanism. APC appears to have potential as a therapeutic agent for prevention of spinal cord injury in patients undergoing aortic aneurysm repair.
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Authors | K Hirose, K Okajima, Y Taoka, M Uchiba, H Tagami, K Nakano, J Utoh, H Okabe, N Kitamura |
Journal | Annals of surgery
(Ann Surg)
Vol. 232
Issue 2
Pg. 272-80
(Aug 2000)
ISSN: 0003-4932 [Print] United States |
PMID | 10903607
(Publication Type: Journal Article)
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Chemical References |
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Topics |
- Animals
- Infarction
(drug therapy)
- Male
- Neutrophil Activation
(drug effects)
- Protein C
(therapeutic use)
- Rats
- Rats, Wistar
- Reperfusion Injury
(mortality, prevention & control)
- Spinal Cord
(blood supply, drug effects, pathology)
- Spinal Cord Injuries
(complications, mortality, pathology, physiopathology, prevention & control)
- Survival Rate
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