General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain.
General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain.
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DOI：
10.1097/aln.0b013e3182303a63
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发表时间：
2011-11
期刊：
影响因子：
8.8
通讯作者：
Jevtovic-Todorovic V
中科院分区：
文献类型：
--
作者：
Sanchez V;Feinstein SD;Lunardi N;Joksovic PM;Boscolo A;Todorovic SM;Jevtovic-Todorovic V
临床上使用的全麻药，无论是单独使用还是联合使用，都会对发育中的哺乳动物大脑造成损害。除了在脆弱的大脑区域引起广泛的细胞凋亡性神经变性外，在突触形成的高峰期全身麻醉还会导致晚年的学习和记忆缺陷。我们在啮齿动物体内的研究表明，固有的(线粒体依赖的)凋亡途径的激活是神经元损伤的最早预警信号，表明线粒体完整性和功能的紊乱可能是最早的触发事件。由于适当和及时的线粒体形态发生对脑发育至关重要，我们研究了常用的麻醉组合(异氟醚、一氧化二氮和咪达唑仑)对幼鼠下丘脑区线粒体的区域分布、超微结构特征、电子传输链功能以及突触神经传递的长期影响。这种麻醉在突触发生的高峰期对线粒体造成长期的损伤，包括线粒体的显著增大(超过30%，p<；0.05)，其结构完整性受损，其复杂的IV活性增加约28%(p<；0.05)，它们在突触前神经元的区域分布(p<；0.05)减少两倍，它们的存在对突触的正常发育和功能至关重要。因此，我们发现，线粒体形态发生受损伴随着自噬活性的增强、线粒体密度的降低(约27%，p<；0.05)和抑制性突触神经传递的长期障碍。这些现象之间的相互关系仍有待确定。发育中的线粒体对全身麻醉非常敏感，可能是麻醉诱导发育性神经变性的重要早期靶点。
Clinically used general anesthetics, alone or in combination, are damaging to the developing mammalian brain. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, exposure to general anesthesia at the peak of synaptogenesis causes learning and memory deficiencies later in life. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage, suggesting that a disturbance in mitochondrial integrity and function could be the earliest triggering events. Since proper and timely mitochondrial morphogenesis is critical for brain development, we examined the long-term effects of a commonly used anesthesia combination (isoflurane, nitrous oxide, and midazolam) on the regional distribution, ultrastructural properties, and electron transport chain function of mitochondria, as well as synaptic neurotransmission, in the subiculum of rat pups. This anesthesia, administered at the peak of synaptogenesis, causes protracted injury to mitochondria, including significant enlargement of mitochondria (over 30%, p < 0.05), impairment of their structural integrity, about 28% increase in their complex IV activity (p < 0.05) and two-fold decrease in their regional distribution in presynaptic neuronal profiles (p < 0.05) where their presence is crucially important for the normal development and functioning of synapses. Consequently, we showed that impaired mitochondrial morphogenesis is accompanied by heightened autophagic activity, decrease in mitochondrial density (about 27%, p < 0.05) and long-lasting disturbances in inhibitory synaptic neurotransmission. The interrelation of these phenomena remains to be established. Developing mitochondria are exquisitely vulnerable to general anesthesia and may be important early target of anesthesia-induced developmental neurodegeneration.