Seven Yasin B, Allen Latoya L, Ciesla Marissa C, Smith Kristin N, Zwick Amanda, Simon Alec K, Holland Ashley E, Santiago Juliet V, Stefan Kelsey, Ross Ashley, Gonzalez-Rothi Elisa J, Mitchell Gordon S
Breathing Research and Therapeutics Center, Department of Physical Therapy and, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Breathing Research and Therapeutics Center, Department of Physical Therapy and, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Neuroscience. 2022 Dec 1;506:38-50. doi: 10.1016/j.neuroscience.2022.10.007. Epub 2022 Oct 20.
Cervical spinal cord injury (cSCI) impairs neural drive to the respiratory muscles, causing life- threatening complications such as respiratory insufficiency and diminished airway protection. Repetitive "low dose" acute intermittent hypoxia (AIH) is a promising strategy to restore motor function in people with chronic SCI. Conversely, "high dose" chronic intermittent hypoxia (CIH; ∼8 h/night), such as experienced during sleep apnea, causes pathology. Sleep apnea, spinal ischemia, hypoxia and neuroinflammation associated with cSCI increase extracellular adenosine concentrations and activate spinal adenosine receptors which in turn constrains the functional benefits of therapeutic AIH. Adenosine 1 and 2A receptors (A, A) compete to determine net cAMP signaling and likely the tAIH efficacy with chronic cSCI. Since cSCI and intermittent hypoxia may regulate adenosine receptor expression in phrenic motor neurons, we tested the hypotheses that: 1) daily AIH (28 days) downregulates A and upregulates A receptor expression; 2) CIH (28 days) upregulates A and downregulates A receptor expression; and 3) cSCI alters the impact of CIH on adenosine receptor expression. Daily AIH had no effect on either adenosine receptor in intact or injured rats. However, CIH exerted complex effects depending on injury status. Whereas CIH increased A receptor expression in intact (not injured) rats, it increased A receptor expression in spinally injured (not intact) rats. The differential impact of CIH reinforces the concept that the injured spinal cord behaves in distinct ways from intact spinal cords, and that these differences should be considered in the design of experiments and/or new treatments for chronic cSCI.
颈脊髓损伤（cSCI）会损害呼吸肌的神经驱动，导致呼吸功能不全和气道保护能力下降等危及生命的并发症。重复性“低剂量”急性间歇性低氧（AIH）是恢复慢性脊髓损伤患者运动功能的一种有前景的策略。相反，“高剂量”慢性间歇性低氧（CIH；约8小时/晚），如睡眠呼吸暂停期间经历的那样，会导致病理变化。与cSCI相关的睡眠呼吸暂停、脊髓缺血、低氧和神经炎症会增加细胞外腺苷浓度并激活脊髓腺苷受体，这反过来又限制了治疗性AIH的功能益处。腺苷1和2A受体（A1、A2A）相互竞争以确定净cAMP信号传导，并可能决定慢性cSCI时tAIH的疗效。由于cSCI和间歇性低氧可能调节膈运动神经元中腺苷受体的表达，我们测试了以下假设：1）每日AIH（28天）下调A1受体并上调A2A受体表达；2）CIH（28天）上调A1受体并下调A2A受体表达；3）cSCI改变CIH对腺苷受体表达的影响。每日AIH对完整或受伤大鼠的两种腺苷受体均无影响。然而，CIH根据损伤状态产生复杂的影响。虽然CIH增加了完整（未受伤）大鼠的A1受体表达，但它增加了脊髓损伤（不完整）大鼠的A2A受体表达。CIH的不同影响强化了这样一个概念，即受伤的脊髓与完整的脊髓表现不同，并且在设计慢性cSCI的实验和/或新治疗方法时应考虑这些差异。
