Kamat Pradip K, Khan Mohammad Badruzzaman, Wood Kristofer, Siddiqui Shahneela, Rudic Daniel R, Dhandapani Krishnan, Waller Jennifer, Hess David C
Departments of Neurology, Medical College of Georgia. Augusta University.
Department of Pharmacology, Medical College of Georgia, Augusta University.
Cond Med. 2021 Dec;4(6):280-284.
Stroke is a leading cause of disability and death worldwide. There is evidence that there is a circadian rhythm in stroke with peak occurrence in the morning (6 to 10 am). However, it is not clear if the size of infarcts and the outcome of stroke also varies during the 24-hour period. We hypothesized that the size of cerebral infarct and outcome from stroke would show circadian variation in a mouse suture occlusion model. Seven to eight-month-old C57BL/6J (n =10-12 mice/group) mice were randomly assigned to undergo middle cerebral artery occlusion (MCAO) for 60 minutes at different time points during the 24h day following zeitgeber time at ZT0, ZT6, ZT12, and Z18. Cerebral blood flow was monitored by Laser Speckle Contrast Imaging at baseline after occlusion, and again at 24h post-occlusion. Neurological deficit was observed by using Bederson score at 24h and 48h. The corner test was used to detect unilateral abnormalities in sensory and motor functions in the stroke mice at 48h. To estimate brain infarction, 2,3,5-tryphenyltetrazolium chloride staining was performed 48h after stroke and the infarct area was quantified using NIH-Image J software. We did not find a significant difference in cerebral blood flow at any time point. There was a significant decrease in neurological deficit as assessed using the Bederson Score from 24h (1.82 ± 1.11) to 48h (1.10 ± 0.12) in the ZT18 (midnight) period (p = 0.0025), however there were no differences between groups at 48h. In the corner test, we found right turn preference significantly higher (p = 0.0348) at noon/ZT06 (9.5 ± 1.06) compared to the fully awake (5.5 ± 4.06) (midnight, ZT18) period and ZT0 (6 am, 4.8 ± 0.97, p = 0.0087). Similarly, the infarction volume was significantly higher (p = 0.0220) during the sleep (ZT06, noon) period (35.22 ± 20.77) than when the ischemic mice were fully awake during the midnight/ZT18 period (15.68 ± 7.54). This is the first report demonstrating that mice have larger infarcts and worse short-term outcomes during their sleep period (noon/ZT06) than during their awake period (midnight/ZT18).
中风是全球致残和致死的主要原因。有证据表明中风存在昼夜节律，早晨（上午6点至10点）发病率最高。然而，尚不清楚梗死灶大小和中风结局在24小时内是否也存在差异。我们假设在小鼠缝线闭塞模型中，脑梗死大小和中风结局会呈现昼夜变化。将7至8月龄的C57BL/6J小鼠（每组10 - 12只）随机分配，在昼夜节律时间ZT0、ZT6、ZT12和ZT18后的24小时内的不同时间点进行大脑中动脉闭塞（MCAO）60分钟。在闭塞后基线时通过激光散斑对比成像监测脑血流量，并在闭塞后24小时再次监测。在24小时和48小时时使用贝德森评分观察神经功能缺损情况。在48小时时使用转角试验检测中风小鼠感觉和运动功能的单侧异常。为了评估脑梗死情况，在中风后48小时进行2,3,5 - 三苯基氯化四氮唑染色，并使用NIH-Image J软件对梗死面积进行定量分析。我们未发现任何时间点的脑血流量有显著差异。在ZT18（午夜）时段，使用贝德森评分评估的神经功能缺损从24小时时的（1.82±1.11）显著下降至48小时时的（1.10±0.12）（p = 0.0025），然而在48小时时各组之间无差异。在转角试验中，我们发现与完全清醒（午夜，ZT18）时段（5.5±4.06）和ZT0（上午6点，4.8±0.97，p = 0.0087）相比，中午/ZT06（9.5±1.06）时右转偏好显著更高（p = 0.0348）。同样，睡眠（ZT06，中午）时段（35.22±20.77）的梗死体积显著高于缺血小鼠在午夜/ZT18时段完全清醒时（15.68±7.54）（p = 0.0220）。这是第一份表明小鼠在睡眠期（中午/ZT06）比清醒期（午夜/ZT18）有更大梗死灶和更差短期结局的报告。
