The immunophilin ligand FK506 attenuates the axonal damage associated withrapid rewarming following posttraumatic hypothermia

Our laboratory has shown that traumatically induced axonal injury (TAI) is significantly reduced by posttraumatic hypothermia followed by slow rewarmi ng. Further, TAI can be exacerbated by rapid rewarming, and the damaging co nsequences of rapid rewarming can be reversed by cyclosporin A, which is be lieved to protect via blunting mitochondrial permeability transition (MPT). In this communication, we continue investigating the damaging consequences of rapid posthypothermic rewarming and the protective role of immunophilin ligands using another member of the immunophilin family, FK506, which does not affect MPT but rather inhibits calcineurin. Rats were subjected to imp act-acceleration brain injury followed by the induction of hypothermia with subsequent rapid or slow posthypothermic rewarming. During rewarming, anim als received either FK506 or its vehicle. Three hours postinjury, animals w ere prepared for the visualization of TAI via antibodies targeting impaired axoplasmic transport (APP) and/or overt neurofilament alteration (RMO-14). Rapid rewarming exacerbated TAI, which was attenuated by FK506. This prote ction was statistically significant for the APP-immunoreactive fibers but n ot for the RMO-14-positive fibers. Combined labeling, using one chromagen t o visualize both axonal changes, suggested that these two immunoreactive pr ofiles revealed two distinct pathologies not occurring along the same axon. Collectively, these studies confirmed previous observations identifying th e adverse consequences of rapid rewarming while also showing the complexity of the pathobiology of TAL Additionally, the demonstration that FK506 is p rotective suggests that calcineurin may be a major target for neuroprotecti on. (C) 2001 Academic Press.