Zhu Yan, Fenik Polina, Zhan Guanxia, Mazza Emilio, Kelz Max, Aston-Jones Gary, Veasey Sigrid C
Center for Sleep and Neurobiology and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2007 Sep 12;27(37):10060-71. doi: 10.1523/JNEUROSCI.0857-07.2007.
The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury were next assessed in major wake-active neural groups. Hypoxia/reoxygenation exposure for 8 weeks resulted in vacuolization in the perikarya and dendrites and markedly impaired c-fos activation response to enforced wakefulness in both noradrenergic locus ceruleus and dopaminergic ventral periaqueductal gray wake neurons. In contrast, cholinergic, histaminergic, orexinergic, and serotonergic wake neurons appeared unperturbed. Six month exposure to hypoxia/reoxygenation resulted in a 40% loss of catecholaminergic wake neurons. Having previously identified NADPH oxidase as a major contributor to wake impairments in hypoxia/reoxygenation, the role of NADPH oxidase in catecholaminergic vulnerability was next addressed. NADPH oxidase catalytic and cytosolic subunits were evident in catecholaminergic wake neurons, where hypoxia/reoxygenation resulted in translocation of p67(phox) to mitochondria, endoplasmic reticulum, and membranes. Treatment with a NADPH oxidase inhibitor, apocynin, throughout hypoxia/reoxygenation exposures conferred protection of catecholaminergic neurons. Collectively, these data show that select wake neurons, specifically the two catecholaminergic groups, can be rendered persistently impaired after long-term exposure to hypoxia/reoxygenation, modeling sleep apnea; wake impairments are irreversible; catecholaminergic neurons are lost; and neuronal NADPH oxidase contributes to this injury. It is anticipated that severe obstructive sleep apnea in humans destroys catecholaminergic wake neurons.
许多患有严重睡眠呼吸暂停的个体存在难治性觉醒障碍，这使我们推测睡眠呼吸暂停中的缺氧/复氧事件会永久性损害觉醒活跃神经元。我们现在证实，成年小鼠长期暴露于缺氧/复氧会导致不可逆的觉醒障碍。接下来，我们评估了主要觉醒活跃神经组的功能和损伤情况。缺氧/复氧暴露8周导致核周体和树突出现空泡化，并且在去甲肾上腺素能蓝斑和多巴胺能腹侧导水管周围灰质觉醒神经元中，对强制觉醒的c-fos激活反应明显受损。相比之下，胆碱能、组胺能、食欲素能和5-羟色胺能觉醒神经元似乎未受影响。缺氧/复氧暴露6个月导致儿茶酚胺能觉醒神经元损失40%。由于之前已确定NADPH氧化酶是缺氧/复氧中觉醒障碍的主要促成因素，接下来研究了NADPH氧化酶在儿茶酚胺能易损性中的作用。NADPH氧化酶催化亚基和胞质亚基在儿茶酚胺能觉醒神经元中很明显，在这些神经元中，缺氧/复氧导致p67(phox)易位至线粒体、内质网和细胞膜。在整个缺氧/复氧暴露期间用NADPH氧化酶抑制剂阿朴吗啡进行治疗，可对儿茶酚胺能神经元起到保护作用。总体而言，这些数据表明，经过长期暴露于缺氧/复氧（模拟睡眠呼吸暂停）后，特定的觉醒神经元，特别是两个儿茶酚胺能组，会持续受损；觉醒障碍是不可逆的；儿茶酚胺能神经元会丢失；并且神经元NADPH氧化酶会导致这种损伤。预计人类严重阻塞性睡眠呼吸暂停会破坏儿茶酚胺能觉醒神经元。
