Departments of Pathology, Division of Neuropathology, Neuroscience, and Anesthesiology and Critical Medicine and the Pathobiology Graduate Training Program, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.
Cells. 2021 Feb 4;10(2):320. doi: 10.3390/cells10020320.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38-38.5 °C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36-36.5 °C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on/12-off or 24 h-on/24 h-off) to lower body temperature (1-3 °C). Cooled ALS mice showed a significant delay in disease onset (103-112 days) compared to normothermia mice (80-90 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 ± 7 days) compared to normothermic mice (135 ± 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，可导致运动神经元变性。目前尚无治疗 ALS 的方法或有效治疗方法。治疗性低温在急性获得性脑损伤的临床治疗中有效，并在手术环境中最小化继发性脑损伤。治疗性低温在慢性神经退行性疾病中的疗效尚未得到检验。我们测试了这样一个假设，即轻度低温/冷适应在表达突变人类基因的 ALS 转基因小鼠模型中是治疗性的。在疾病的无症状阶段，与同窝对照相比，突变雄性小鼠的体温（口腔和轴向）持续高热（38-38.5°C），但在疾病终末期，小鼠通常体温过低（36-36.5°C）。在无症状阶段，通过环境控制室（12 小时 ON/12 小时 OFF 或 24 小时 ON/24 小时 OFF）使突变型小鼠（清醒自由移动）适应全身轻度低温，以降低体温（1-3°C）。与正常体温小鼠（80-90 天）相比，冷却的 ALS 小鼠的疾病发作明显延迟（103-112 天），并且在运动表现方面的功能下降明显减弱。与未冷却的小鼠相比，在 80 天时检查的冷却小鼠的运动神经元损失、线粒体肿胀和脊髓炎症减少。冷却可减轻骨骼肌中热休克蛋白 70、线粒体解偶联蛋白-3 和 SUMO1 缀合蛋白的丢失，并使线粒体通透性转换孔失活。与正常体温小鼠（135±4 天）相比，冷却的 ALS 小鼠的寿命显著延长（148±7 天）。因此，间歇性全身轻度低温对 ALS 小鼠具有治疗作用，在中枢神经系统和骨骼肌中具有保护作用，靶向线粒体。
