The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: Neuroprotection and local regeneration

There is considerable evidence that immunophilin ligands can promote the re generation of axons in peripheral nerves and act as neuroprotective agents in the CNS. We have examined the effects of FK506 and GPI 1046 on the respo nses to partial transection of ascending spinal dorsal column axons at T9, in some cases combined with crush of one sciatic nerve. FK506 (0.5 or 2.0 m g/kg) and GPI 1046 (10 or 40 mg/kg) was administered subcutaneously immedia tely after surgery and five times a week thereafter. Some animals received methylprednisolone (MP) (two subcutaneous doses of 30 mg/kg) in addition to , or instead of, FK506. After survival times of 1-12 weeks, dorsal column a xons were labeled transganglionically with cholera toxin B-HRP. There was m assive axonal sprouting at the lesion sites in animals with sciatic nerve i njury and immunophilin ligand treatment. In FK506-treated animals a few sev ered sensory axons regenerated for up to 10 mm rostral to the lesion. Of gr eater significance, 30% of 71 FK506-treated animals had spared axons in the dorsal column, extending to the nucleus gracilis, versus 8% of 50 control animals (P < 0.05), showing that FK506 reduces the likelihood of axonal des truction due to secondary injury. A combination of FK506 and MP afforded gr eater protection than MP alone (P < 0.05), but axonal survival was not affe cted by sciatic nerve crush, dose of FK506, or survival time after injury. GPI 1046 (n = 11) did not promote axonal survival. Thus FK506 protects axon s from secondary injury following spinal cord trauma, and in this experimen tal model, its neuroprotective effect is greater than that of MP. (C) 1999 Academic Press.