Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Department of Anesthesiology, Chiba Rosai Hospital, Ichihara 299-0003, Japan.
Int J Mol Sci. 2020 Jan 10;21(2):450. doi: 10.3390/ijms21020450.
Preclinical studies have shown that exposure of the developing brain to inhalational anesthetics can cause neurotoxicity. However, other studies have claimed that anesthetics can exert neuroprotective effects. We investigated the mechanisms associated with the neurotoxic and neuroprotective effects exerted by inhalational anesthetics. Neuroblastoma cells were exposed to sevoflurane and then cultured in 1% oxygen. We evaluated the expression of proteins related to the unfolded protein response (UPR). Next, we exposed adult mice in which binding immunoglobulin protein (BiP) had been mutated, and wild-type mice, to sevoflurane, and evaluated their cognitive function. We compared our results to those from our previous study in which mice were exposed to sevoflurane at the fetal stage. Pre-exposure to sevoflurane reduced the expression of CHOP in neuroblastoma cells exposed to hypoxia. Anesthetic pre-exposure also significantly improved the cognitive function of adult wild-type mice, but not the mutant mice. In contrast, mice exposed to anesthetics during the fetal stage showed cognitive impairment. Our data indicate that exposure to inhalational anesthetics causes endoplasmic reticulum (ER) stress, and subsequently leads to an adaptive response, the UPR. This response may enhance the capacity of cells to adapt to injuries and improve neuronal function in adult mice, but not in developing mice.
临床前研究表明，发育中的大脑暴露于吸入麻醉剂会引起神经毒性。然而，其他研究则声称麻醉剂可以发挥神经保护作用。我们研究了与吸入麻醉剂的神经毒性和神经保护作用相关的机制。将神经母细胞瘤细胞暴露于七氟醚中，然后在 1%氧气中培养。我们评估了与未折叠蛋白反应（UPR）相关的蛋白质的表达。接下来，我们使结合免疫球蛋白蛋白（BiP）发生突变的成年小鼠和野生型小鼠暴露于七氟醚中，并评估了它们的认知功能。我们将我们的结果与我们之前的研究进行了比较，该研究中，在胎儿期使小鼠暴露于七氟醚中。七氟醚预先暴露可降低缺氧条件下神经母细胞瘤细胞中 CHOP 的表达。麻醉前暴露还显著改善了成年野生型小鼠的认知功能，但对突变型小鼠没有改善。相比之下，在胎儿期暴露于麻醉剂的小鼠则表现出认知障碍。我们的数据表明，暴露于吸入麻醉剂会引起内质网（ER）应激，随后会引起适应性反应，即 UPR。这种反应可能会增强细胞适应损伤的能力，并改善成年小鼠的神经元功能，但不会改善发育中的小鼠。
