Büki A, Koizumi H, Povlishock J T
Department of Anatomy, Medical College of Virginia, Richmond, Virginia, 23298-0709, USA.
Exp Neurol. 1999 Sep;159(1):319-28. doi: 10.1006/exnr.1999.7139.
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 side-arm modification associated with neurofilament compaction (NFC) evolving to axonal disconnection. Recent observations have suggested that moderate hypothermia is neuroprotective in several models of TBI. Nevertheless, the pathway by which hypothermia prevents traumatic axonal injury (TAI) is still a matter of debate. The present study was conducted to evaluate the effects of moderate, early posttraumatic hypothermia on calpain-mediated spectrin proteolysis (CMSP), implicated in the pathogenesis of TAI. Using moderate (32 degrees C) hypothermia of 90 min duration without rewarming, the density of CMSP immunoreactive/damaged axons was quantified via LM analysis in vulnerable brain stem fiber tracts of hypothermic and normothermic rats subjected to impact acceleration TBI (90 min postinjury survival). To assess the influence of posthypothermic rewarming, a second group of animals was subjected to 90 min of hypothermia followed by 90 min of rewarming to normothermic levels when CMSP was analyzed to detect if any purported CMSP prevention persisted (180 min postinjury 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 employed. 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 results suggest that the neuroprotective effects of hypothermia in TBI are associated with the inhibition of axonal/cytoskeletal damage.
动物和人类的创伤性脑损伤（TBI）会导致广泛的轴突损伤，其特征为局灶性轴膜通透性改变、钙蛋白酶介导的蛋白水解作用以及与神经丝压缩（NFC）相关的神经丝侧臂修饰，进而发展为轴突离断。最近的观察结果表明，在几种TBI模型中，适度低温具有神经保护作用。然而，低温预防创伤性轴突损伤（TAI）的途径仍存在争议。本研究旨在评估创伤后早期适度低温对钙蛋白酶介导的血影蛋白水解作用（CMSP）的影响，CMSP与TAI的发病机制有关。在不进行复温的情况下，对遭受撞击加速性TBI（伤后存活90分钟）的低温和常温大鼠的易损脑干纤维束进行光镜分析，通过该分析对持续90分钟的适度（32摄氏度）低温下CMSP免疫反应性/受损轴突的密度进行定量。为了评估低温后复温的影响，在分析CMSP以检测是否存在任何所谓的CMSP预防作用持续存在（伤后存活180分钟）时，对第二组动物进行90分钟的低温处理，然后复温至常温水平90分钟。此外，为了确定这种保护作用是否转化为在显示CMSP降低的相同病灶中具有可比的细胞骨架保护作用，还使用了针对改变/压缩的NF亚基的抗体。伤后急性期应用适度低温在两个时间点均显著减少了显示CMSP的受损轴突数量，并在伤后180分钟显著降低了NFC免疫反应性。这些结果表明，低温在TBI中的神经保护作用与抑制轴突/细胞骨架损伤有关。
