Targeting L-Selectin to Improve Neurologic and Urologic Function After Spinal Cord Injury
Technical Report,30 Sep 2014,29 Sep 2015
University of California, San Francisco San Francisco United States
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Purpose We are evaluating the efficacy of diclofenac DFA, an anti-inflammatory agent with L-Selectin sheddase activity, in a murine model of spinal cord injury.Scope These studies have focused on the efficacy of DFA in the context of dose, optimal therapeutic window, and dependency on injury severity, using clinically relevant outcome measures that include neurologic assessments and assays of bladder function.Major findings -We demonstrated that 40 mgkg DFA is the minimally effective dose to induce L-selectin shedding in a mouse model of spinal cord injury -We demonstrated locomotor recovery in mice receiving 40mgkg DFA up to 3 hours following spinal cord injury -We demonstrated improved locomotor recovery using this paradigm for two injury severities, mild and severe, suggesting a robust therapeutic effect -We identified no adverse effects to animal health, as evaluated by body weight -We identified no added locomotor recovery due to multiple, successive doses of DFA. Moreover, additional doses proved to be toxic and increase animal mortality -We have demonstrated improved white matter sparing in mice receiving 40 mgkg DFA for up to 3 hours following spinalcord injury -We have demonstrated reduced lesion volume in mice receiving 40 mgkg DFA up to 3 hours following spinal cord injury. -We have demonstrated no adverse effects of DFA on bladder function following spinal cord injury. However, the drug resulted in no improvement in bladder function Significance We have identified robust locomotor recovery in both mild and severe spinal cord injured mice that received DFA up to 3 hours following injury. Furthermore, we identified no adverse effects utilizing this dose. Therefore, these promising data suggest that 40mgkg DFA, administered within 3 hours of spinal cord injury, as a single dose could be an effective therapeutic intervention for spinal cord injury.