Protective conditioning of the brain: expressway or roadblock?

Abstract

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.

Figure 1. ‘Conditioning’ paradigms to protect the brain

Typically, preconditioning uses a sublethal stimulus given minutes or days before the insult against which it aims to protect. Stuttering reperfusion is the prototypical per- or postconditioning strategy, by which one aims to prevent ‘reperfusion damage’ by repetitively opening and blocking brain perfusion before permanent reperfusion is allowed. Remote ischaemia is another per- or postconditioning strategy which typically produces repetitive, short phases of ischaemia of a peripheral limb to induce humoral and neural mechanisms of protection of a remote organ, such as the brain. Pharmacological mimics are drugs that either boost endogenous protective signalling cascades (such as the HIF pathway), or exogenously provide the effectors of endogenous protection, such as EPO.

Figure 2. General principles of action of ‘conditioning strategies’ to protect the brain

A pre-, per-, post-, remote-conditioning stimulus may either: directly protect the brain via release of locally or remotely acting metabolites (e.g. adenosine); after activation of sensors (e.g. HIF-1) lead to a complex signalling cascade which may include genetic as well as epigenetic responses; or activate genetic and epigenetic responses via neuronal pathways (e.g. activating the sympathetic nervous system or the hypothalamic–pituitary axis). The signalling pathways of the various conditioning strategies may converge in similar or even identical effector mechanisms, such as suppressed death pathways, induced survival pathways, decreased metabolism (‘hibernation’), and increased substrate delivery.