Jackson Travis C, Kochanek Patrick M
1 John G. Rangos Research Center, UPMC Children's Hospital of Pittsburgh, Safar Center for Resuscitation Research, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
2 Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
Ther Hypothermia Temp Manag. 2019 Mar;9(1):13-47. doi: 10.1089/ther.2019.0001. Epub 2019 Feb 25.
Three decades of animal studies have reproducibly shown that hypothermia is profoundly cerebroprotective during or after a central nervous system (CNS) insult. The success of hypothermia in preclinical acute brain injury has not only fostered continued interest in research on the classic secondary injury mechanisms that are prevented or blunted by hypothermia but has also sparked a surge of new interest in elucidating beneficial signaling molecules that are increased by cooling. Ironically, while research into cold-induced neuroprotection is enjoying newfound interest in chronic neurodegenerative disease, conversely, the scope of the utility of therapeutic hypothermia (TH) across the field of acute brain injury is somewhat controversial and remains to be fully defined. This has led to the era of Targeted Temperature Management, which emphasizes a wider range of temperatures (33-36°C) showing benefit in acute brain injury. In this comprehensive review, we focus on our current understandings of the novel neuroprotective mechanisms activated by TH, and discuss the critical importance of developmental age germane to its clinical efficacy. We review emerging data on four cold stress hormones and three cold shock proteins that have generated new interest in hypothermia in the field of CNS injury, to create a framework for new frontiers in TH research. We make the case that further elucidation of novel cold responsive pathways might lead to major breakthroughs in the treatment of acute brain injury, chronic neurological diseases, and have broad potential implications for medicines of the distant future, including scenarios such as the prevention of adverse effects of long-duration spaceflight, among others. Finally, we introduce several new phrases that readily summarize the essence of the major concepts outlined by this review-namely, Ultramild Hypothermia, the "Responsivity of Cold Stress Pathways," and "Hypothermia in a Syringe."
三十年的动物研究反复表明，低温在中枢神经系统（CNS）损伤期间或之后具有显著的脑保护作用。低温在临床前急性脑损伤中的成功不仅激发了人们对经典继发性损伤机制研究的持续兴趣，这些机制可被低温预防或减弱，还引发了对阐明因降温而增加的有益信号分子的新兴趣。具有讽刺意味的是，虽然对冷诱导神经保护作用的研究在慢性神经退行性疾病中受到了新的关注，但相反，治疗性低温（TH）在急性脑损伤领域的效用范围存在一定争议，仍有待充分界定。这导致了目标温度管理时代的到来，该时代强调在急性脑损伤中显示有益效果的更广泛温度范围（33 - 36°C）。在这篇全面综述中，我们重点关注目前对TH激活的新型神经保护机制的理解，并讨论发育年龄与其临床疗效的关键相关性。我们回顾了关于四种冷应激激素和三种冷休克蛋白的新数据，这些数据在CNS损伤领域引发了对低温的新兴趣，以创建TH研究新前沿的框架。我们认为，进一步阐明新型冷反应途径可能会在急性脑损伤、慢性神经疾病的治疗方面取得重大突破，并对遥远未来的药物有广泛的潜在影响，包括预防长期太空飞行的不良反应等情况。最后，我们引入了几个新短语，它们可以轻松概括本综述所概述的主要概念的本质，即超轻度低温、“冷应激途径的反应性”和“注射器中的低温”。
