Short-term inhibition of fibrinolytic system restores locomotor function after spinal cord injury in mice.

Abstract

Spinal cord injury (SCI) is caused by an initial mechanical insult followed by a series of deleterious events that promote the progressive damage of affected tissues. Fibrinolysis, the process by which plasmin degrades cross-linked fibrin clots, has numerous functions in the central nervous system. However, the roles of the fibrinolytic system in SCI pathophysiology remain unknown. We investigated the roles of fibrinolysis in SCI, and explored therapeutic applications targeting fibrinolysis. Plasminogen-deficient (Plg-/-) mice exhibited significantly improved locomotor function in the early phase of SCI (the first 7 days post injury), with significant inhibition of bleeding and vascular permeability, but failed to demonstrate conclusive functional recovery. Consistent with these findings, the short-term administration of tranexamic acid (TXA) in wild-type mice over the first 3 days post injury significantly improved locomotor function after SCI, whereas prolonged TXA administration did not. Prolonged TXA administration resulted in significantly lower levels of matrix metalloproteinase activities in the spinal cord, suggesting that inhibition of the fibrinolytic system impaired tissue remodeling. Our results indicate that the fibrinolytic system has time-dependent biphasic actions following SCI. The temporally optimised modulation of fibrinolytic activity may thus be a novel therapeutic strategy to improve functional outcomes after SCI.

• Authors: Yasuyuki Shiraishi, Atsushi Kimura, Osamu Matsuo, Yoichi Sakata, Katsushi Takeshita, Tsukasa Ohmori
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 16024 (11 05 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31690812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Cytokines
• Tranexamic Acid
• Plasminogen
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Acute Disease
• Animals
• Chemokines (metabolism)
• Cytokines (metabolism)
• Fibrinolysis (drug effects)
• Locomotion (physiology)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plasminogen (deficiency, genetics)
• Recovery of Function (drug effects)
• Spinal Cord (metabolism, pathology)
• Spinal Cord Injuries (metabolism, pathology)
• Tranexamic Acid (pharmacology)