Sebastiani Anne, Gölz Christina, Werner Christian, Schäfer Michael K E, Engelhard Kristin, Thal Serge C
Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University , Mainz, Germany .
J Neurotrauma. 2015 Oct 15;32(20):1599-607. doi: 10.1089/neu.2014.3751. Epub 2015 Jun 30.
Traumatic brain injury (TBI) initiates an excessive mediator release of e.g. neurotrophins, which promote neuronal survival, differentiation, and modulate synaptic plasticity. Paradoxically, mature forms of neurotrophins promote neuronal survival, whereas unprocessed forms of neurotrophins induce cell death through p75 neurotrophin receptor (p75NTR) signaling. p75NTR is widely expressed during synaptogenesis and is subsequently downregulated in adulthood. Repair mechanisms after acute cerebral insults can reactivate its expression. Therefore, the influence of p75NTR on secondary brain damage was addressed. mRNA levels of p75NTR and its ligands were quantified in brain tissue up to 7 days after experimental TBI (controlled cortical impact; CCI). Brain damage, motor function and inflammatory marker gene expression were determined in mice lacking the proneurotrophin-binding site of the p75NTR protein (NGFR(-/-)) and wild type littermates (NGFR(+/+)) 24 h and 5 days after CCI. In addition, the effect of TAT-Pep5 (pharmacological inhibitor of the intracellular p75NTR death domain) on lesion volume was evaluated 24 h after insult. p75NTR mRNA levels were induced nine-fold by TBI. In NGFR(-/-) mice, lesion volume was reduced by 29% at 24 h and by 21% 5 days after CCI. Motor coordination was significantly improved 24 h after trauma compared with the wild type. Pharmacological inhibition of the p75NTR signaling reduced lesion volume by 18%. The present study presents first time evidence that genetic mutation of the neurotrophin interaction site of p75NTR strongly limits post-traumatic cell death. In addition, we revealed pharmacological targeting of the intracellular p75NTR cell death domain as a promising approach to limit acute brain damage.
创伤性脑损伤（TBI）会引发例如神经营养因子等过多介质的释放，这些介质可促进神经元存活、分化并调节突触可塑性。矛盾的是，成熟形式的神经营养因子可促进神经元存活，而未加工形式的神经营养因子则通过p75神经营养因子受体（p75NTR）信号传导诱导细胞死亡。p75NTR在突触形成过程中广泛表达，随后在成年期下调。急性脑损伤后的修复机制可使其表达重新激活。因此，研究了p75NTR对继发性脑损伤的影响。在实验性TBI（控制性皮质撞击；CCI）后长达7天的脑组织中，对p75NTR及其配体的mRNA水平进行了定量分析。在CCI后24小时和5天，对缺乏p75NTR蛋白原神经营养因子结合位点（NGFR(-/-)）的小鼠和野生型同窝小鼠（NGFR(+/+)）的脑损伤、运动功能和炎症标志物基因表达进行了测定。此外，在损伤后24小时评估了TAT-Pep5（细胞内p75NTR死亡结构域的药理抑制剂）对损伤体积的影响。TBI可使p75NTR mRNA水平升高9倍。在NGFR(-/-)小鼠中，CCI后24小时损伤体积减少29%，5天后减少21%。与野生型相比，创伤后24小时运动协调性显著改善。对p75NTR信号传导的药理抑制可使损伤体积减少18%。本研究首次证明，p75NTR神经营养因子相互作用位点的基因突变可强烈限制创伤后细胞死亡。此外，我们还揭示了对细胞内p75NTR细胞死亡结构域进行药理靶向治疗是限制急性脑损伤的一种有前景的方法。
