1Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 2Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 3Mouse Behavioral Outcome Unit of the Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 4Focus Program Translational Neurosciences (FTN) of the Johannes Gutenberg-University, Mainz, Germany.
Crit Care Med. 2016 Feb;44(2):e70-82. doi: 10.1097/CCM.0000000000001284.
The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice.
Randomized laboratory animal study.
University research laboratory.
Adult C57BL/6N and nerve growth factor receptor-deficient mice.
Sedation by IV propofol bolus application delayed after controlled cortical impact injury.
Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor.
This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.
γ-氨基丁酸调节剂异丙酚通过 p75 神经营养因子受体信号通路破坏神经营养因子稳态，导致健康未成熟大脑中的神经元细胞死亡。在成年期，p75 神经营养因子受体下调，异丙酚失去其神经毒性作用。然而，急性脑损伤等急性脑损伤会重新激活类似发育的程序，并增加 p75 神经营养因子受体的表达，可能促进修复过程，这反过来又会使大脑对异丙酚介导的神经毒性敏感。本研究探讨了在成年小鼠实验性创伤性脑损伤后 p75 神经营养因子受体表达高峰时延迟单次推注异丙酚对其的影响。
随机实验室动物研究。
大学研究实验室。
成年 C57BL/6N 和神经生长因子受体缺陷小鼠。
在皮质撞击伤后给予 IV 异丙酚推注镇静。
创伤性脑损伤后 24 小时给予异丙酚镇静可增加损伤体积，增强钙蛋白酶诱导的αII- spectrin 裂解，并增加损伤周围组织的细胞死亡。应用 CatWalk（Noldus Information Technology，Wageningen，The Netherlands）步态分析测定伤后 30 天的运动功能，发现异丙酚镇静组动物明显受损。异丙酚增强了 pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor 比值，加重了 p75 神经营养因子受体介导的细胞死亡。用 p75 神经营养因子受体细胞死亡结构域的药理学抑制剂（TAT-Pep5）和缺乏 p75 神经营养因子受体细胞外神经营养因子结合位点的小鼠均可消除异丙酚的毒性。
本研究首次提供证据表明，急性脑损伤后异丙酚镇静可能产生有害影响，并提示 pro-brain-derived neurotrophic factor/p75 神经营养因子受体途径发挥作用。这一观察结果很重要，因为异丙酚和其他具有 GABA 受体活性的化合物在急性脑病理患者中常被用于镇静或手术和介入治疗。
