The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia
The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia
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DOI：
10.1213/01.ane.0000223671.49376.b2
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发表时间：
2006-08-01
影响因子：
5.7
通讯作者：
Fahlman, Christian S.
中科院分区：
文献类型：
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作者：
Bickler, Philip E.;Fahlman, Christian S.
我们测试了吸入麻醉剂异氟烷对缺氧神经元的保护是否与MAP激酶和抗凋亡辅助因子的Ca 2+依赖性磷酸化有关。在培养的小鼠皮层神经元中，我们测量了缺氧或缺氧联合异氟烷（气相中1%）后Ca 2+依赖性和Ca 2+非依赖性MAP激酶、转录因子和凋亡调节因子磷酸化的变化。在缺氧神经元中，异氟烷使细胞死亡和TUNEL染色减少> 80%。异氟烷从细胞内储存释放Ca 2+，使含氧神经元中的[Ca 2 +]（i）增加约20%。神经保护与缺氧神经元中[Ca 2 +]（i）的较小增加相关，并需要IP 3受体和磷脂酶C。在缺氧神经元中，异氟烷增加了Ca 2+依赖性MAP激酶Pyk 2和p42/44（ERK）的磷酸化。非钙依赖性MAP激酶p38通路显示异氟烷磷酸化增加，但不与离子霉素，钙离子载体。在异氟烷存在下，JNK在缺氧神经元中磷酸化，转录因子c-fun也是如此;用SP 600125抑制JNK可防止c-jun磷酸化和神经保护作用。异氟烷降低了促凋亡辅因子Bad和p90 RSK的磷酸化，并增加了Akt的磷酸化。然而，除了c-jun，转录因子（Elk-1，GSK-3，Forkhead，p90 RSK）减少或保持不变。我们的结论是，异氟烷的保护缺氧皮层神经元涉及的信号，包括细胞内Ca 2+调节的变化，几个MAP激酶通路和调变的凋亡调节。
We tested whether the protection of hypoxic neurons by the inhaled anesthetic isoflurane is related to the Ca2+-dependent phosphorylation of MAP kinases and anti-apoptotic co-factors. In cultures of mouse cortical neurons we measured changes in the phosphorylation of Ca2+-dependent and Ca2+-independent MAP kinases, transcription factors, and apoptosis regulators after hypoxia or hypoxia combined with isoflurane (1% in gas phase). In hypoxic neurons, isoflurane reduced cell death and TUNEL staining by > 80%. Isoflurane released Ca2+ from intracellular stores, increasing [Ca2+](i) in oxygenated neurons by approximately 20%. Neuroprotection was associated with a smaller increase in [Ca2+](i) in hypoxic neurons and required IP3 receptors and phospholipase C. In hypoxic neurons, isoflurane increased the phosphorylation of the Ca2+-dependent MAP kinases Pyk2 and p42/44 (ERK). The Ca2+-independent MAP kinase p38 pathway showed increased phosphorylation with isoflurane but not with ionomycin, a Ca2+ ionophore. JNK was phosphorylated in hypoxic neurons in the presence of isoflurane, as was the transcription factor c-fun; JNK inhibition with SP600125 prevented both phosphorylation of c-jun and neuroprotection. Isoflurane decreased phosphorylation of the pro-apoptotic cofactors Bad and p90RSK and increased Akt phosphorylation. However, with the exception of c-jun, transcription factors (Elk-1, GSK-3, Forkhead, p90RSK) decreased or remained unchanged. We conclude that isoflurane's protection of hypoxic cortical neurons involves signaling that includes changes in intracellular Ca2+ regulation, several MAP kinase pathways and modulation of apoptosis regulators.