1 Department of Neurology, School of Medicine, University of California , Irvine, California.
2 Department of Anatomy & Neurobiology, School of Medicine, University of California , Irvine, California.
J Neurotrauma. 2017 Oct 1;34(19):2823-2832. doi: 10.1089/neu.2016.4852. Epub 2017 Jun 16.
Cardiac arrest (CA) affects >550,000 people annually in the United States whereas 80-90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery, but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from CA-related neurological impairments, including arousal deficits. Using an asphyxial CA and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid (CSF) and orexin-expressing neurons. We also conduct pharmacological inhibition of orexin post-resuscitation. We show that recovery from neurological deficits begins between 4 and 24 h post-resuscitation, with additional recovery by 72 h post-resuscitation. Orexin-A levels in the CSF are lowest during periods of poorest arousal post-resuscitation (4 h) and recover to control levels by 24 h. Immunostaining revealed that the number of orexin-A immunoreactive neurons declined at 4 h post-resuscitation, but increased to near normal levels by 24 h. There were no significant changes in the number of neurons expressing melanin-concentrating hormone, another neuropeptide localized in similar hypothalamus regions. Last, administration of the dual orexin receptor antagonist, suvorexant, during the initial 24 h post-resuscitation, led to sustained neurological deficits. The orexin pathway is critical during early phases of neurological recovery post-CA. Blocking this early action leads to persistent neurological deficits. This is of considerable clinical interest given that suvorexant recently received U.S. Food and Drug Administration approval for insomnia treatment.
心脏骤停 (CA) 影响美国每年 >550,000 人，而 80-90%的幸存者处于昏迷状态。从昏迷中觉醒对于恢复至关重要，但觉醒机制尚未确定。orexin-A 是一种下丘脑兴奋性神经肽，与各种脑损伤中的觉醒缺陷有关。我们研究了 orexinergic 系统在与 CA 相关的神经损伤恢复中的作用，包括觉醒缺陷。我们使用大鼠窒息性 CA 和复苏模型，结合脑脊液 (CSF) 中 orexin-A 水平和 orexin 表达神经元的变化，研究了复苏后神经恢复情况。我们还在复苏后进行了 orexin 的药理学抑制。我们发现，从神经功能缺损中恢复始于复苏后 4 至 24 小时之间，72 小时后进一步恢复。复苏后最差觉醒期（4 小时）CSF 中的 orexin-A 水平最低，24 小时后恢复至对照水平。免疫染色显示，复苏后 4 小时 orexin-A 免疫反应性神经元数量减少，但 24 小时后增加至接近正常水平。表达黑色素浓缩激素的神经元数量没有明显变化，黑色素浓缩激素是另一种位于类似下丘脑区域的神经肽。最后，在复苏后最初 24 小时内给予双重 orexin 受体拮抗剂苏沃雷生，导致持续的神经功能缺损。在 CA 后神经恢复的早期阶段，orexin 途径至关重要。阻断这种早期作用会导致持续的神经功能缺损。鉴于苏沃雷生最近获得美国食品和药物管理局批准用于治疗失眠症，这具有重要的临床意义。
