TY - JOUR
T1 - The immunophilin ligand FK506 attenuates the axonal damage associated with rapid rewarming following posttraumatic hypothermia
AU - Suehiro, Eiichi
AU - Singleton, Richard H.
AU - Stone, James R.
AU - Povlishock, John T.
N1 - Funding Information:
This work is supported by Grant NS 20193. We thank Susan Walker, Lynn Davis, and Thomas Coburn for their excellent technical support.
PY - 2001
Y1 - 2001
N2 - Our laboratory has shown that traumatically induced axonal injury (TAI) is significantly reduced by posttraumatic hypothermia followed by slow rewarming. Further, TAI can be exacerbated by rapid rewarming, and the damaging consequences of rapid rewarming can be reversed by cyclosporin A, which is believed 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 impact-acceleration brain injury followed by the induction of hypothermia with subsequent rapid or slow posthypothermic rewarming. During rewarming, animals received either FK506 or its vehicle. Three hours postinjury, animals were 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 protection was statistically significant for the APP-immunoreactive fibers but not for the RMO-14-positive fibers. Combined labeling, using one chromagen to visualize both axonal changes, suggested that these two immunoreactive profiles revealed two distinct pathologies not occurring along the same axon. Collectively, these studies confirmed previous observations identifying the adverse consequences of rapid rewarming while also showing the complexity of the pathobiology of TAI. Additionally, the demonstration that FK506 is protective suggests that calcineurin may be a major target for neuroprotection.
AB - Our laboratory has shown that traumatically induced axonal injury (TAI) is significantly reduced by posttraumatic hypothermia followed by slow rewarming. Further, TAI can be exacerbated by rapid rewarming, and the damaging consequences of rapid rewarming can be reversed by cyclosporin A, which is believed 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 impact-acceleration brain injury followed by the induction of hypothermia with subsequent rapid or slow posthypothermic rewarming. During rewarming, animals received either FK506 or its vehicle. Three hours postinjury, animals were 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 protection was statistically significant for the APP-immunoreactive fibers but not for the RMO-14-positive fibers. Combined labeling, using one chromagen to visualize both axonal changes, suggested that these two immunoreactive profiles revealed two distinct pathologies not occurring along the same axon. Collectively, these studies confirmed previous observations identifying the adverse consequences of rapid rewarming while also showing the complexity of the pathobiology of TAI. Additionally, the demonstration that FK506 is protective suggests that calcineurin may be a major target for neuroprotection.
KW - FK506
KW - Hypothermia
KW - RMO-14
KW - Rewarming
KW - Traumatic axonal injury
KW - β-amyloid precursor protein (APP)
UR - http://www.scopus.com/inward/record.url?scp=0035214649&partnerID=8YFLogxK
U2 - 10.1006/exnr.2001.7765
DO - 10.1006/exnr.2001.7765
M3 - Article
C2 - 11681852
AN - SCOPUS:0035214649
SN - 0014-4886
VL - 172
SP - 199
EP - 210
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -