Combinational therapy using hypothermia and the immunophilin ligand FK506 to target altered pial arteriolar reactivity, axonal damage, and blood-brain barrier dysfunction after traumatic brain injury in rat.

This study evaluated the utility of combinational therapy, coupling delayed posttraumatic hypothermia with delayed FK506 administration, on altered cerebral vascular reactivity, axonal injury, and blood-brain barrier (BBB) disruption seen following traumatic brain injury (TBI). Animals were injured, subjected to various combinations of hypothermic/FK506 intervention, and equipped with cranial windows to assess pial vascular reactivity to acetylcholine. Animals were then processed with antibodies to the amyloid precursor protein and immunoglobulin G to assess axonal injury and BBB disruption, respectively. Animals were assigned to five groups: (1) sham injury plus delayed FK506, (2) TBI, (3) TBI plus delayed hypothermia, (4) TBI plus delayed FK506, and (5) TBI plus delayed hypothermia with FK506. Sham injury plus FK506 had no impact on vascular reactivity, axonal injury, or BBB disruption. Traumatic brain injury induced dramatic axonal injury and altered pial vascular reactivity, while triggering local BBB disruption. Delayed hypothermia or FK506 after TBI provided limited protection. However, TBI with combinational therapy achieved significantly enhanced vascular and axonal protection, with no BBB protection. This study shows the benefits of combinational therapy, using posttraumatic hypothermia with FK506 to attenuate important features of TBI. This suggests that hypothermia not only protects but also extends the therapeutic window for improved FK506 efficacy.