Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea.
Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, South Korea.
J Neurochem. 2021 Jan;156(1):76-87. doi: 10.1111/jnc.15121. Epub 2020 Jul 18.
While recent studies strongly suggest that a single, short anesthetic exposure does not affect neurodevelopment, the effects of multiple exposures remain unclear. Unfortunately, studying "multiple exposures" is challenging as it is an extremely heterogeneous descriptor comprising diverse factors. One potentially important, but unrecognized factor is the interval between anesthetic exposures. In order to evaluate the significance of interval, we exposed post-natal day 16, 17 mice to three sevoflurane exposures (2.5%, 1 hr) with short (2 hr) or long (24 hr) intervals. Changes in synaptic transmission, plasticity, protein expression, and behavior were assessed in male and female mice. We discovered that short-interval exposures induced a female-dependent decrease in miniature inhibitory post-synaptic current (mIPSC) frequency 5 days after the last exposure (control: 18.44 ± 2.86 Hz, sevoflurane:14.65 ± 4.54 Hz). Short-interval sevoflurane exposed mice also displayed long-term behavioral deficits at adult age (hypoactivity, anxiety). These behavioral changes were consistent with the sex-dependent changes in inhibitory transmission, as they were more robust in female mice. Although there was no change in learning and memory, short-interval sevoflurane exposures also impaired LTP in a non-sex-dependent manner (control: 171.10 ± 26.90%, sevoflurane: 149.80 ± 26.48 %). Most importantly, we were unable to find long-lasting consequences in mice that received long-interval sevoflurane exposures. Our study provides novel insights regarding the significance of the interval between multiple exposures, and also suggests that the neurotoxic effects of multiple anesthetic exposures may be reduced by simply increasing the interval between each exposure.
虽然最近的研究强烈表明，单次短暂的麻醉暴露不会影响神经发育，但多次暴露的影响仍不清楚。不幸的是，研究“多次暴露”具有挑战性，因为它是一个极其异质的描述符，包含多种因素。一个潜在的重要但未被认识的因素是麻醉暴露之间的间隔。为了评估间隔的意义，我们在出生后第 16 天和第 17 天，用 2.5%的七氟醚对 17 只小鼠进行了三次麻醉暴露（1 小时），间隔时间为 2 小时或 24 小时。我们在雄性和雌性小鼠中评估了突触传递、可塑性、蛋白质表达和行为的变化。我们发现，短间隔暴露会导致雌性小鼠在最后一次暴露后 5 天，出现抑制性突触后电流（mIPSC）频率降低（对照：18.44±2.86Hz，七氟醚：14.65±4.54Hz）。短间隔七氟醚暴露的小鼠在成年时也表现出长期的行为缺陷（活动减少，焦虑）。这些行为变化与抑制性传递的性别依赖性变化一致，因为它们在雌性小鼠中更为明显。尽管学习和记忆没有改变，但短间隔七氟醚暴露也以非性别依赖的方式损害 LTP（对照：171.10±26.90%，七氟醚：149.80±26.48%）。最重要的是，我们在接受长间隔七氟醚暴露的小鼠中没有发现长期后果。我们的研究提供了关于多次暴露间隔意义的新见解，并表明通过简单地增加每次暴露之间的间隔，多次麻醉暴露的神经毒性影响可能会降低。
