Ketamine: The best partner for isoflurane in neonatal anesthesia?
Ketamine: The best partner for isoflurane in neonatal anesthesia?
复制标题
氯胺酮：异氟烷在新生儿麻醉中的最佳搭档？
DOI：
10.1016/j.mehy.2008.07.035
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Luo, Ailin
中科院分区：
文献类型：
--
作者：
Xiang, Qiang;Tan, Lei;Luo, Ailin
异氟醚是新生儿麻醉中最常用的吸入麻醉药之一。已经表明，当以临床相关浓度应用于发育中的大脑时，异氟烷可以诱导半胱天冬酶活化和细胞凋亡。最近的研究表明，临床相关的异氟醚治疗可通过激活内质网（ER）膜1，4，5-三磷酸肌醇（IP 3）受体，产生过量的钙从ER释放到细胞质并触发细胞凋亡来诱导神经变性和细胞凋亡。虽然异氟醚诱导细胞凋亡的确切机制仍需进一步研究，但普遍认为胞浆游离钙水平的增加是主要的危险因素。已有研究发现，在出生后早期，GABA（A）受体的激活可减轻N-甲基-D-天冬氨酸（NMDA）通道的电压依赖性Mg ~（2+）阻滞，并通过增强NMDA通道的Ca ~（2+）内流而增加细胞内Ca ~（2+）水平;而在成年大鼠，可增强NMDA通道的电压依赖性Mg ~（2+）阻滞，减少Ca ~（2+）内流。由于异氟烷以激动性方式作用于GABA（A）受体，因此我们推测异氟烷不仅通过激活内质网（ER）膜中的IP 3受体，而且通过激活GABA（A）受体并使突触后膜去极化以促进NMDA受体介导的Ca 2+内流来增加新生神经元中的细胞内钙。同时，我们假设广泛使用的小儿麻醉剂氯胺酮作为NMDA型谷氨酸受体的非竞争性拮抗剂，可能是异氟醚在新生儿麻醉中的最佳搭档，因为它不仅通过阻断NMDA受体，而且通过抑制细胞质中肌醇三磷酸的形成。(C)2008爱思唯尔有限公司版权所有。
Isoflurane is one of the most commonly used inhalation anesthetic in neonatal anaesthesia. It has been suggested that isoflurane can induce caspase activation and apoptosis when applied in a clinically relevant concentration in the developing brain. Recent researches have indicated that a clinically relevant isoflurane treatment may induce neurodegeneration and apoptosis by activating the endoplasmic reticulum (ER) membrane inositol 1,4,5-trisphosphate (IP3) receptor, producing excessive calcium release from ER to the cytoplasm and triggering apoptosis. Although the exact mechanism by which isoflurane induces apoptosis still needs further study, it is generally accepted that the increase of cytosolic free calcium levels is the major risk factor. Previous studies have found that during early postnatal life, activation of gamma-aminobutyric acid (GABA(A)) receptor reduces the voltage-dependent Mg2+ block of N-methyl-D-aspartate (NMDA) channels in neurons and increases cytosolic calcium levels by potentiated the Ca2+ influx through NMDA channels; while in the adult, it may enhance the voltage-dependent Mg2+ block of NMDA channels and decrease the Ca2+ influx through NMDA channels. Since isoflurane acts at the GABA(A) receptor in an agonistic manner, here we presume that isoflurane increases intracellular calcium in neonatal neurons not only by activating IP3 receptors in the endoplasmic reticulum (ER) membrane, but also by activating the GABA(A) receptor and depolarizing the postsynaptic membrane enough to facilitate NMDA receptor-mediated Ca2+ influx. Meanwhile, we hypothesized that ketamine, a widely used pediatric anesthetic, acts as a noncompetitive antagonist of the NMDA type of glutamate receptors, which may be the best partner for isoflurane in neonatal anesthesia for it may attenuate isoflurane-induced caspase activation and apoptosis in the neonatal neurons by inhibiting the isoflurane-induced elevation in cytosolic calcium not only by blocking the NMDA receptors, but also by suppressing inositol triphosphate formation in the cytoplasm. (C) 2008 Elsevier Ltd. All rights reserved.