BARROW Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ, USA; Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.
Department of Child Health, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; Department of Biology and Biochemistry, University of Bath, Bath, UK.
Exp Neurol. 2020 May;327:113242. doi: 10.1016/j.expneurol.2020.113242. Epub 2020 Feb 11.
Sleep-wake disturbances are both a risk factor and reported morbidity for intracerebral hemorrhage (ICH). ICH begins with a ruptured blood vessel and blood leakage into the parenchyma. In response to initial damage, pathophysiological processes ensue that both exacerbate and repair damage. Inflammation is a hallmark process of ICH, which includes microglia activation and increased cytokine signaling. Due to the dual role of cytokines as inflammatory signaling proteins and sleep regulatory substances (SRSs), we hypothesized that ICH would activate microglia, increase SRSs, and alter sleep-wake patterns following an experimental model of ICH in the mouse. Male mice were randomized to receive an injection of collagenase (ICH; n = 8) or saline (sham; n = 11) in the striatum of the right hemisphere. Sleep-wake activity was recorded for 6 full days after ICH via noninvasive sleep cages. Blood and tissue were collected at 7 days after ICH to quantify pro-inflammatory cytokines/SRSs (IL-1β, TNF-α, IL-6) and microglia deramification by skeleton analysis. There was an overall injury effect on sleep in mice subjected to ICH at the transition from dark (wake) to light (sleep) at 2, 3, 4, 5, and 6 days after ICH compared with shams. Further analysis confirmed that ICH mice had significantly earlier wake offsets at the dark/light transition and more robust circadian patterns of wake behavior than saline control mice. Spatiotemporal skeleton analysis indicated an increase in microglial cell number with a decrease in endpoints per cell (decreased ramification) for the ipsilateral ICH perihematomal region compared with saline control. There were no changes to plasma cytokine levels at 7 days after ICH when comparing each condition. This is the first known study to show changes in sleep-wake patterns after experimental ICH. Elucidation of mechanisms that link sleep, inflammation, and ICH offers new pharmacological opportunities and rehabilitative strategies to improve recovery in stroke patients.
睡眠-觉醒障碍既是脑出血 (ICH) 的风险因素，也是其报告发病率。ICH 始于血管破裂和血液渗漏到实质中。在初始损伤的反应中，病理生理过程随之而来，既加重又修复损伤。炎症是 ICH 的一个标志过程，包括小胶质细胞激活和细胞因子信号增加。由于细胞因子作为炎症信号蛋白和睡眠调节物质 (SRS) 的双重作用，我们假设 ICH 会在小鼠的 ICH 实验模型中激活小胶质细胞，增加 SRS，并改变睡眠-觉醒模式。雄性小鼠被随机分为胶原酶组 (ICH；n=8) 或盐水组 (假手术；n=11)，右侧纹状体注射。ICH 后通过非侵入性睡眠笼记录 6 天的睡眠-觉醒活动。ICH 后 7 天收集血液和组织，通过骨骼分析定量促炎细胞因子/SRSs (IL-1β、TNF-α、IL-6) 和小胶质细胞形态变化。与假手术相比，ICH 小鼠在 ICH 后第 2、3、4、5 和 6 天从暗 (觉醒) 到亮 (睡眠) 的过渡期间，整体上对睡眠有损伤作用。进一步分析证实，ICH 小鼠在暗/亮转换时的觉醒起始明显更早，与盐水对照相比，清醒行为的昼夜节律模式更强。时空骨骼分析表明，与盐水对照相比，同侧 ICH 血肿周围区域的小胶质细胞数量增加，而每个细胞的终点减少 (分支减少)。比较每种情况时，ICH 后 7 天血浆细胞因子水平没有变化。这是第一项已知的研究，表明实验性 ICH 后睡眠-觉醒模式发生变化。阐明睡眠、炎症和 ICH 之间的联系机制为改善中风患者的康复提供了新的药物治疗机会和康复策略。
