Moderate posttraumatic hypothermia decreases early calpain-mediated proteolysis and concomitant cytoskeletal compromise in traumatic axonal injury

Traumatic brain injury (TBI) in animals and man generates widespread axonal injury characterized by focal axolemmal permeability changes, induction of calpain-mediated proteolysis, and neurofilament sidearm modification assoc iated with neurofilament compaction (NFC) evolving to axonal disconnection. Recent observations have suggested that moderate hypothermia is neuroprote ctive in several models of TBI. Nevertheless, the pathway by which hypother mia prevents traumatic axonal injury (TAI) is still a matter of debate. The present study was conducted to evaluate the effects of moderate, early pos ttraumatic hypothermia on calpain-mediated spectrin proteolysis (CMSP), imp licated in the pathogenesis of TAT. Using moderate (32 degrees C) hypotherm ia of 90 min duration without rewarming, the density of CMSP immunoreactive /damaged axons was quantified via LM analysis in vulnerable brain stem fibe r tracts of hypothermic and normothermic rats subjected to impact accelerat ion TBI (90 min postinjury survival). To assess the influence of posthypoth ermic rewarming, a second group of animals was subjected to 90 min of hypot hermia followed by 90 min of rewarming to normothermic levels when CMSP was analyzed to detect if any purported CMSP prevention persisted (180 min pos tinjury survival). Additionally, to determine if this protection translated into comparable cytoskeletal protection in the same foci showing decreased CMSP, antibodies targeting altered/compacted NF subunits were also employe d. Moderate hypothermia applied in the acute postinjury period drastically reduced the number of damaged axons displaying CMSP at both time points and significantly reduced NFC immunoreactivity at 180 min postinjury. These re sults suggest that the neuroprotective effects of hypothermia in TBI are as sociated with the inhibition of axonal/cytoskeletal damage. (C) 1999 Academ ic Press.