The genetics of isoflurane-induced developmental neurotoxicity.
The genetics of isoflurane-induced developmental neurotoxicity.
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DOI：
10.1016/j.ntt.2016.10.012
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发表时间：
2017-03
影响因子：
2.9
通讯作者：
Morgan PG
中科院分区：
文献类型：
--
作者：
Na HS;Brockway NL;Gentry KR;Opheim E;Sedensky MM;Morgan PG
早期发育暴露于挥发性麻醉剂诱导的神经毒性是广泛物种中生物体的特征，从线虫C.到哺乳动物。预防麻醉诱导的神经毒性（AIN）将依赖于对其潜在机制的理解。然而，没有进行正向遗传筛选来确定AIN中受影响的关键途径。通过表征这些途径，我们可以确定消除哺乳动物中异氟烷诱导的AIN的机制。成虫趋化性线虫幼虫暴露于异氟烷后的AIN用于测量AIN。我们最初比较了已知影响神经系统发育的经典突变体之间的趋化性指数的变化，根据数据添加突变体。使用荧光标记物可视化特定基因的激活。然后用雷帕霉素处理动物或用异氟烷预处理动物以测试对AIN的影响。44个突变，以及药理学操作，确定了两个途径，从无脊椎动物到人类高度保守，调节C。优雅一种应激保护途径（依赖于β 2）的激活消除了AIN，而第二种应激反应途径（内质网（ER）相关应激）的激活导致AIN。对雷帕霉素机制靶点（mTOR）的药理学抑制阻断ER应激和AIN。在幼虫暴露前用异氟烷预处理也抑制AIN。我们的数据最好用一个模型来解释，在这个模型中，异氟烷急性抑制线粒体功能，导致反应激活，最终导致ER应激。异氟烷的神经毒性作用可以通过在控制这种反应的通路中的多个点进行操作来完全预防。内源性信号通路可用于保护生物体免受异氟烷的神经毒性作用。
Neurotoxicity induced by early developmental exposure to volatile anesthetics is a characteristic of organisms across a wide range of species, extending from the nematode C. elegans to mammals. Prevention of anesthetic-induced neurotoxicity (AIN) will rely upon an understanding of its underlying mechanisms. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. By characterizing such pathways, we may identify mechanisms to eliminate isoflurane induced AIN in mammals. Chemotaxis in adult C. elegans after larval exposure to isoflurane was used to measure AIN. We initially compared changes in chemotaxis indices between classical mutants known to affect nervous system development adding mutants in response to data. Activation of specific genes was visualized using fluorescent markers. Animals were then treated with rapamycin or preconditioned with isoflurane to test effects on AIN. Forty-four mutations, as well as pharmacologic manipulations, identified two pathways, highly conserved from invertebrates to humans, that regulate AIN in C. elegans. Activation of one stress-protective pathway (DAF-2 dependent) eliminates AIN, while activation of a second stress-responsive pathway (endoplasmic reticulum (ER) associated stress) causes AIN. Pharmacologic inhibition of the mechanistic Target of Rapamycin (mTOR) blocks ER-stress and AIN. Preconditioning with isoflurane prior to larval exposure also inhibited AIN. Our data are best explained by a model in which isoflurane acutely inhibits mitochondrial function causing activation of responses that ultimately lead to ER-stress. The neurotoxic effect of isoflurane can be completely prevented by manipulations at multiple points in the pathways that control this response. Endogenous signaling pathways can be recruited to protect organisms from the neurotoxic effects of isoflurane.