Mergenthaler Philipp, Dirnagl Ulrich
Center for Stroke Research Berlin (CSB), Department of Neurology and Experimental Neurology, Charité - University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany.
J Physiol. 2011 Sep 1;589(17):4147-55. doi: 10.1113/jphysiol.2011.209718. Epub 2011 Jun 27.
The brain responds to noxious stimulation with protective signalling. Over the last decades, a number of experimental strategies have been established to study endogenous brain protection. Pre-, per-, post- and remote 'conditioning' are now widely used to unravel the underlying mechanisms of endogenous neuroprotection. Some of these strategies are currently being tested in clinical trials to protect the human brain against anticipated damage or to boost protective responses during or after injury. Here we summarize the principles of 'conditioning' research and current efforts to translate this knowledge into effective treatment of patients. Conditioning to induce protected brain states provides an experimental window into endogenous brain protection and can lead to the discovery of drugs mimicking the effects of conditioning. Mechanisms of endogenous brain tolerance can be activated through a wide variety of stimuli that signal 'danger' to the brain. These danger signals lead to the induction of regulator and effector mechanisms, which suppress death and induce survival pathways, decrease metabolism, as well as increase substrate delivery. We conclude that preclinical research on endogenous brain protection has greatly benefited from conditioning strategies, but that clinical applications are challenging, and that we should not prematurely rush into ill-designed and underpowered clinical trials.
大脑通过保护性信号对有害刺激做出反应。在过去几十年里，已经建立了许多实验策略来研究内源性脑保护。预适应、围适应、后适应和远隔“适应”现在被广泛用于揭示内源性神经保护的潜在机制。其中一些策略目前正在临床试验中进行测试，以保护人类大脑免受预期损伤，或在损伤期间或损伤后增强保护反应。在这里，我们总结了“适应”研究的原则以及目前将这些知识转化为有效治疗患者的努力。诱导受保护脑状态的适应为内源性脑保护提供了一个实验窗口，并可能导致发现模拟适应效果的药物。内源性脑耐受机制可以通过向大脑发出“危险”信号的多种刺激来激活。这些危险信号导致调节和效应机制的诱导，这些机制抑制死亡并诱导生存途径，降低代谢，并增加底物供应。我们得出结论，内源性脑保护的临床前研究从适应策略中受益匪浅，但临床应用具有挑战性，我们不应过早地仓促开展设计不佳和效力不足的临床试验。
