Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats

J Neurotrauma. 2005 Oct;22(10):1150-61. doi: 10.1089/neu.2005.22.1150.

Abstract

We have previously shown that FK506 accelerates the rate of nerve regeneration in the peripheral nervous system (PNS) and increases regeneration of central nervous system (CNS) axons into a peripheral nerve graft. In the present study, we examined whether FK506 and a nonimmunosuppressive derivative (FK1706) improve functional recovery and long distance regeneration following a hemisection lesion of spinal cord at T10/T11. Rats were given daily subcutaneous injections of either FK506 (2 mg/kg/day), FK1706 (2 mg/kg/day), an equivalent volume of saline or 30% DMSO as vehicle, respectively. Functional recovery was assessed using a modified Tarlov/Klinger scale, walking along progressively narrower wooden beams (7.7-1.7 cm widths), and analysis of footprints obtained during walking. Compared to both control groups, FK506 and FK1706-treated animals demonstrated significant functional recovery 4 days (beam walking), 2 weeks (footprints), and 4 weeks (Tarlov/Klinger scale). By 11 weeks, FK506-treated and FK1706-treated animals were able to walk, albeit poorly, along even the narrowest (1.7 cm) beam. At 11 weeks, the spinal cords were re-exposed and a small piece of gel foam-soaked Fluoro-Gold was placed on the injured side 2-cm caudal to the first injury. Five days later, the animals were perfused and tissues prepared for fluorescence microscopy. FK506-treated and FK1706-treated rats demonstrate a significantly greater number of retrogradely labeled neurons in the red nucleus. The results implicate a nonimmunosuppressant mechanism in FK506's action and suggest that FK506 or a nonimmunosuppressant derivative may be useful for treatment of spinal cord injuries.

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / pathology
  • Axotomy
  • Functional Laterality
  • Immunohistochemistry
  • Male
  • Microscopy, Fluorescence
  • Nerve Regeneration / drug effects
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function / drug effects*
  • Red Nucleus / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / pathology
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / immunology
  • Spinal Cord Injuries / pathology
  • Tacrolimus / analogs & derivatives*
  • Tacrolimus / therapeutic use*

Substances

  • FK1706
  • Neuroprotective Agents
  • Tacrolimus