中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (7): 1244-1251.doi: 10.4103/1673-5374.301031

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

阿托西汀或氟西汀延迟治疗结合有限的自主跑步可促进脑缺血小鼠运动功能的恢复

  

  • 出版日期:2021-07-15 发布日期:2021-01-07
  • 基金资助:

    这项工作得到了美国国家卫生研究院对VTK(1R01NS106879)的研究资助的部分支持

Delayed atomoxetine or fluoxetine treatment coupled with limited voluntary running promotes motor recovery in mice after ischemic stroke

Faisal F. Alamri1, †, Abdullah Al Shoyaib1, Nausheen Syeara1, Anisha Paul1, Srinidhi Jayaraman1, Serob T. Karamyan2, Thiruma V. Arumugam3, Vardan T. Karamyan1, 4, *   

  1. 1 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA;  2 Department of Pharmacology, Faculty of Pharmacy, Yerevan State Medical University, Yerevan, Armenia;  3 Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Australia;  4 Center for Blood Brain Barrier Research, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA † Current address: College of Sciences and Health Profession, King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
  • Online:2021-07-15 Published:2021-01-07
  • Contact: Vardan T. Karamyan, PhD, vardan.karamyan@ttuhsc.edu.
  • Supported by:
    This work was partly supported by a National Institutes of Health research grant to VTK (1R01NS106879).

摘要:

目前的治疗策略对于脑卒中后功能恢复的促进效果尚不令人满意。为评估和比较阿托西汀或氟西汀延迟治疗(从脑缺血后第5天开始)结合有限的运动训练(脑缺血后第9-42天,每天2小时自主转轮运动)对光化学栓塞法建立缺血性脑卒中小鼠模型运动功能恢复的作用。实验主要通过网格行走和汽缸测试两项自发运动行为任务评估小鼠运动功能。同时实验量化了整个研究过程中的跑步距离和速度,以及内侧颗粒状皮质和梗死体积中小白蛋白阳性神经元的数量。结果显示,有限的运动训练或单独的药物治疗均不能显著促进脑缺血小鼠运动功能的恢复。但是,运动训练与任何一种药物的结合都可以在脑缺血后42天促进运动功能的恢复,尤以阿托西汀作用更为明显。运动功能恢复小鼠的同侧内侧颗粒皮质中小白蛋白阳性抑制性中间神经元显著减少,且各药物干预和运动训练组间的脑梗死体积相当。以上结果表明,阿托西汀或氟西汀治疗与有限的运动训练相结合可以为难以完成早期高强度物理治疗的脑卒中患者提供治疗手段。

https://orcid.org/0000-0003-0050-6047 (Vardan T. Karamyan)

Abstract: Currently, there is an unmet need for treatments promoting post-stroke functional recovery. The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy (starting on post-stroke day 5), coupled with limited physical exercise (2 hours daily voluntary wheel running; post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic stroke. These drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to stroke. The predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests. Additionally, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct volumes. Both sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after stroke. However, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent drug. This was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental groups. If further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity physiotherapy. Furthermore, in light of the recently completed Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) and Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS) trials, our observations call for newly designed studies where fluoxetine or atomoxetine pharmacotherapy is evaluated in combination with structured physical rehabilitation rather than alone. This study was approved by the Texas Tech University Health Sciences Center Institutional Animal Care and Use Committee (protocol # 16019).

Key words: drug repurposing, neural repair, physical exercise, physiotherapy, post-stroke recovery, pre-clinical trial, FLAME trial, selective norepinephrine reuptake inhibitor, selective serotonin reuptake inhibitor, stroke pharmacotherapy