Targeting L-Selectin To Improve Neurologic and Urologic Function after Spinal Cord Injury
Abstract
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 a mouse model of spinal cord injury and 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: 40 mg/kg, i.p. of DFA is the minimally effective dose to induce L-selectin shedding after spinal cord injury; 40mg/kg DFA, i.p, administered up to at least 3 hours post injury results in a significant improvement in locomotor recovery after either mild or severe injuries, a finding that speaks to the robust therapeutic effect of this drug; There were no adverse effects to animal health, as evaluated by body weight; There was no added locomotor recovery due to multiple, successive doses of DFA. Moreover, additional doses proved to betoxic and increased animal mortality; 40 mg/kg, i.p. of DFA, given up to 3 hours post injury, resulted in a long-term improvement in white matter sparing and reduced lesion volume; While DFA did not improve long-term bladder function, nor did it exacerbate bladder dysfunction after injury. 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 DFA, administered within at least 3 hours of spinal cord injury, could be an effective therapeutic intervention for human spinal cord injury. We recognize that the dose in mice far exceeds what is safe for humans.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2016
- Accession Number
- AD1031939
Entities
People
- Adia F. Martinez
- Alpa Mahuvakar
- Christopher J. Sontag
- Dylan A. Mccreedy
- Linda J. Noble
- Thomas Fandel
Organizations
- University of California, San Francisco