Milanovic Desanka, Pesic Vesna, Loncarevic-Vasiljkovic Natasa, Pavkovic Zeljko, Popic Jelena, Kanazir Selma, Jevtovic-Todorovic Vesna, Ruzdijic Sabera
Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
Neurotox Res. 2016 Oct;30(3):434-52. doi: 10.1007/s12640-016-9629-1. Epub 2016 May 17.
A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2 weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20 mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24 h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.
多项实验研究报告称，在快速突触形成阶段，将常用的临床麻醉剂应用于2周龄以下的幼鼠时，会诱导广泛的神经细胞凋亡和认知障碍。丙泊酚是临床实践中最常用的全身麻醉剂，其对发育中大脑的神经毒性机制仍有待深入研究。本研究调查了不同暴露时间的丙泊酚麻醉对Fas受体和Fas配体表达的影响，这两种物质介导大脑中的促凋亡和促炎信号传导。将丙泊酚（20mg/kg）以足以维持2小时、4小时和6小时麻醉时长的多剂量给予7日龄大鼠。在麻醉结束后的0小时、4小时、16小时和24小时处死动物。结果发现，丙泊酚麻醉诱导Fas/FasL和下游caspase-8在丘脑的表达比在皮质中更显著。相反，内在途径激活的标志物Bcl-2和caspase-9在皮质中受丙泊酚治疗的影响更大。此外，我们证实了caspase-1和IL-1β细胞因子转录上调以及随后小胶质细胞的激活，这可能与脑部炎症有关。行为分析显示，新生期暴露于丙泊酚的P35和P60动物在旷场试验连续三天的测试中运动活性显著更高，尽管未阻止会话间习惯化的形成。这些数据与我们之前的结果共同有助于阐明丙泊酚对发育中大脑毒性的复杂机制。
