Nishio S, Yunoki M, Chen Z F, Anzivino M J, Lee K S
Department of Neuroscience, University of Virginia, Charlottesville, USA.
J Neurosurg. 2000 Nov;93(5):845-51. doi: 10.3171/jns.2000.93.5.0845.
Ischemic neuronal damage associated with neurological and other types of surgery can have severe consequences for functional recovery after surgery. Hypothermia administered during and/or after ischemia has proved to be clinically beneficial and its effects often rival or exceed those of other therapeutic strategies. In the present study the authors examined whether transient hypothermia is an effective preconditioning stimulus for inducing ischemic tolerance in the brain.
Adult rats were subjected to a 20-minute period of hypothermic preconditioning followed by an interval ranging from 6 hours to 7 days. At the end of this interval, the animals were subjected to transient focal ischemia induced by clamping one middle cerebral artery and both carotid arteries for 1 hour. The volume of cerebral infarction was assessed 1 or 7 days postischemia. In the first series of experiments, hypothermic preconditioning (28.5 degrees C) with a postconditioning interval of 1 day reduced the extent of cerebral infarction measured 1 and 7 days postischemia. In the second series, hypothermic preconditioning (31.5 degrees C) with postconditioning intervals of 6 hours, 1 day, or 2 days (but not 7 days) reduced the extent of cerebral infarction measured 1 day postischemia. Treatment with the protein synthesis inhibitor anisomycin blocked the protective effect of hypothermic preconditioning. In a final series of experiments, in vitro brain slices prepared from hypothermia-preconditioned (nonischemic) animals were shown to tolerate a hypoxic challenge better than slices prepared from unconditioned animals.
These findings indicate that hypothermic preconditioning induces a form of delayed tolerance to focal ischemic damage. The time course over which tolerance occurs and the ability of a protein synthesis inhibitor to block tolerance suggest that increased expression of one or more gene products is necessary to establish tissue tolerance following hypothermia. The attenuation of hypoxic injury in vitro following in vivo preconditioning indicates that tolerance is due, at least in part, to direct effects on the brain neuropil. Hypothermic preconditioning could provide a relatively low-risk approach for improving surgical outcome after invasive surgery, including high-risk neurological and cardiovascular procedures.
与神经外科手术及其他类型手术相关的缺血性神经元损伤会对术后功能恢复产生严重后果。已证明在缺血期间和/或之后给予低温治疗具有临床益处，其效果常常与其他治疗策略相当或更优。在本研究中，作者探究了短暂低温是否为诱导脑缺血耐受的有效预处理刺激。
成年大鼠接受20分钟的低温预处理，随后间隔6小时至7天。在此间隔结束时，通过夹闭一侧大脑中动脉和双侧颈动脉1小时诱导动物发生短暂局灶性缺血。在缺血后1天或7天评估脑梗死体积。在第一组实验中，低温预处理（28.5摄氏度）且预处理间隔为1天可减少缺血后1天和7天测得的脑梗死范围。在第二组实验中，低温预处理（31.5摄氏度）且预处理间隔为6小时、1天或2天（但不是7天）可减少缺血后1天测得的脑梗死范围。蛋白质合成抑制剂茴香霉素治疗可阻断低温预处理的保护作用。在最后一组实验中，与未预处理动物制备的脑片相比，由低温预处理（非缺血）动物制备的体外脑片显示出对缺氧刺激的耐受性更好。
这些发现表明低温预处理可诱导对局灶性缺血损伤的一种延迟耐受形式。耐受发生的时间进程以及蛋白质合成抑制剂阻断耐受的能力表明，一种或多种基因产物表达增加对于低温后建立组织耐受是必要的。体内预处理后体外缺氧损伤的减轻表明，耐受至少部分归因于对脑髓质的直接作用。低温预处理可为改善包括高风险神经外科和心血管手术在内的侵入性手术后的手术结果提供一种相对低风险的方法。
