FK1706, a novel non-immunosuppressant neurophilin ligand, ameliorates motor dysfunction following spinal cord injury through its neuroregenerative action

Eur J Pharmacol. 2008 Sep 4;591(1-3):147-52. doi: 10.1016/j.ejphar.2008.06.064. Epub 2008 Jun 20.

Abstract

Injured spinal cord axons fail to regenerate in part due to a lack of trophic support. While various methods for replacing neurotrophins have been pursued, clinical uses of these methods face significant barriers. FK1706, a non-immunosuppressant neurophilin ligand, potentiates nerve growth factor signaling, suggesting therapeutic potential for functional deficits following spinal cord injury. Here, we demonstrate that FK1706 significantly improves behavioral outcomes in animal models of spinal cord hemisection and contusion injuries in rats. Furthermore, we show that FK1706 is effective even if administration is delayed until 1 week after injury, suggesting that FK1706 has a reasonable therapeutic time-window. Morphological analysis of injured axons in the dorsal corticospinal tract showed an increase in the radius and perimeter of stained axons, which were reduced by FK1706 treatment, suggesting that axonal swelling and retraction balls observed in injured spinal cord were improved by the neurotrophic effect of FK1706. Taken together, FK1706 improves both behavioral motor function and the underlying morphological changes, suggesting that FK1706 may have therapeutic potential in meeting the significant unmet needs in spinal cord injury.

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • Disease Models, Animal
  • Immunophilins / pharmacology
  • Male
  • Nerve Growth Factor / drug effects
  • Nerve Growth Factor / metabolism
  • Nerve Regeneration / drug effects*
  • Neuroprotective Agents / pharmacology*
  • Pyramidal Tracts / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects
  • Signal Transduction / drug effects
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / physiopathology
  • Tacrolimus / analogs & derivatives*
  • Tacrolimus / pharmacology
  • Time Factors

Substances

  • FK1706
  • Neuroprotective Agents
  • Nerve Growth Factor
  • Immunophilins
  • Tacrolimus