Neuroprotection in cerebral ischaemia: Facts and fancies - The need for new approaches
Neuroprotection in cerebral ischaemia: Facts and fancies - The need for new approaches
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DOI：
10.1159/000074808
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发表时间：
2004-01-01
影响因子：
2.9
通讯作者：
Ahmed, N
中科院分区：
文献类型：
--
作者：
Wahlgren, NG;Ahmed, N
“神经保护”是一个术语，用来描述保护大脑免受病理损伤的干预措施的假定效果。在闭塞性中风中，神经保护的概念包括抑制缺血条件下发生的一系列病理分子事件，导致钙内流、激活自由基反应和细胞死亡。本文将对神经保护试验、有关神经保护的一些事实和设想、脑缺血的病理生理学以及人类神经保护卒中试验明显失败的可能原因进行综述。事实：在闭塞性中风的急性期，适度的血流减少会导致脑细胞的“半暗带”，通常围绕着核心梗塞，在这种情况下，脑细胞可以存活几个小时，但如果再灌注不成立，脑细胞就会逐渐死亡。随着对急性缺血性卒中复杂病理生理机制认识的增加，大量神经保护性干预措施应运而生。许多神经保护剂在动物模型中被证明是有效的，但到目前为止，还没有人类研究表明在主要终点指标上对急性缺血性中风患者有统计学意义的益处。一些神经保护剂在事后分析中显示出有益的效果，一些研究仍在进行中。幻想：在中风的神经保护研究的早期，人们认为一种几乎没有副作用的药物可以在送往医院的路上由救护车工作人员给予，并在临床上对预后产生显著影响。由于只有好处，没有风险，将不再需要神经学家的诊断技能和神经放射学评估。为什么神经保护剂在人类卒中试验中失败？有几种可能的解释，为什么神经保护试验一直无法证明效果，除了可能的基本概念是错误的。神经保护剂对梗塞面积的影响是时间依赖的，而且治疗通常比成功的实验性中风模型开始得晚得多。药物剂量不足和目标区域药物供应缓慢可能是其他原因。试验样本量太小和具有预测意义的重要基线变量的不平衡是试验方法学缺陷的例子。我们可以做些什么呢？未来的新方法：在动物模型中，神经保护候选者的临床前测试应该标准化。年轻而健康的动物建立的传统卒中模型可能会被共同发病的老年动物所取代，如动脉粥样硬化。需要发现高效的新神经保护剂，并尝试联合治疗。在临床试验中，最有可能成功的可能是神经保护概念，涉及缺血和再灌注病理生理学机制，结合溶栓治疗方案。神经保护剂，可能是药物的组合，最好接近这些机制中的几种。治疗应及早开始，至少在卒中发病后3小时内通过静脉途径进行。选定的化合物(S)应该很容易通过血脑屏障。在中风模型中被证明是高度有效的神经保护剂应该是首选的，实验使用的剂量也应该在临床环境中使用。试验应该使用随机化技术，减少具有预测意义的重要基线变量的不平衡，试验的估计样本量应该基于对适度临床效果的预期。版权所有(C)2004 S.Karge
'Neuroprotection' is a term used to describe the putative effect of interventions protecting the brain from pathological damage. In occlusive stroke, the concept of neuroprotection involves inhibition of a cascade of pathological molecular events occurring under ischaemia and leading to calcium influx, activation of free radical reactions and cell death. This article will summarize neuroprotection trials to date, some facts and fancies about neuroprotection, ischaemic pathophysiology and possible reasons for the apparent failure of human neuroprotective stroke trials. Facts: In the acute stage of occlusive stroke, moderate reduction of blood flow results in a 'penumbra' of brain cells, often surrounding a core infarct, in which brain cells survive for a few hours but gradually die if reperfusion is not established. Increased knowledge of the complex pathophysiology in acute ischaemic stroke has led to the development of a great number of candidates for neuroprotective interventions. Many neuroprotective agents have proven efficacious in animal models, but so far no human study has shown a statistically significant benefit in patients with acute ischaemic stroke on primary endpoint measures. Some neuroprotective agents show beneficial effects on post hoc analyses, and some studies are still ongoing. Fancies: In the early years of neuroprotective studies in stroke, it was thought that a drug with almost no adverse effects could be given by ambulance staff on the way to hospital and induce a clinically significant effect on outcome. Since there were only benefits and no risks, diagnostic skills by neurologists and neuroradiological evaluations would no longer be required. Why Have Neuroprotective Agents Failed in Human Stroke Trials? There are several possible explanations why neuroprotective trials have been unable to prove an effect in addition to the eventuality that the basic concept is wrong. The effects of neuroprotective agents on infarct size are time dependent, and treatment has often been initiated much later than in successful experimental stroke models. Insufficient doses of the drugs and slow availability of the drug at the target area may be other explanations. Too small sample sizes in trials and imbalance of prognostically important baseline variables are examples of shortcomings in trial methodology. What Can Be Done? Future New Approaches: In animal models, preclinical testing of neuroprotective candidates should be standardized. Conventional stroke models with young and healthy animals may be replaced by older animals with common co-morbidity such as atherosclerosis. Highly effective new neuroprotective agents need to be discovered, and combination therapies should be tried. In clinical trials, the greatest chances of success may be with neuroprotective concepts involving mechanisms in both ischaemic and reperfusion pathophysiology, in combination with a thrombolytic therapy protocol. Neuroprotective agents, possibly combinations of agents, should preferably approach several of these mechanisms. Treatments should be initiated early, at least within 3 h after stroke onset, by an intravenous route. The selected compound( s) should easily pass the blood-brain barrier. Neuroprotective agents shown to be highly effective in stroke models should be preferred, and doses used experimentally should be used also in the clinical setting. Trials should use randomization techniques, which reduce imbalances of prognostically important baseline variables, and the estimated sample size of a trial should be based on expectations of a modest clinical effect. Copyright (C) 2004 S. Karge