title: Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats.
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.
authors.affiliation: Center for Research on Occupational & Environmental Toxicology, Oregon Health Sciences University, Portland, OR 97201-3098, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Voda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamaji
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Gold
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D019771:Axotomy; D007839:Functional Laterality; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D009416:Nerve Regeneration / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D012012:Red Nucleus / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; C505380:FK1706; D016559:Tacrolimus