Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use

Abstract

Neuroprotection and brain repair in patients after acute brain damage are still major unfulfilled medical needs. Pharmacological treatments are either ineffective or confounded by adverse effects. Consequently, endogenous mechanisms by which the brain protects itself against noxious stimuli and recovers from damage are being studied. Research on preconditioning, also known as induced tolerance, over the past decade has resulted in various promising strategies for the treatment of patients with acute brain injury. Several of these strategies are being tested in randomised clinical trials. Additionally, research into preconditioning has led to the idea of prophylactically inducing protection in patients such as those undergoing brain surgery and those with transient ischaemic attack or subarachnoid haemorrhage who are at high risk of brain injury in the near future. In this Review, we focus on the clinical issues relating to preconditioning and tolerance in the brain; specifically, we discuss the clinical situations that might benefit from such procedures. We also discuss whether preconditioning and tolerance occur naturally in the brain and assess the most promising candidate strategies that are being investigated.

Figure 1. Comparison of conventional and preconditioning neuroprotection trials

Note that the preconditioning trial enables a complete baseline assessment and leads to organ protection before ischaemia (or trauma).

Figure 2. Signalling cascades of preconditioning

Various stimuli lead to protection via modules of sensors, transducers, and effectors. Adapted from Dirnagl et al, with permission from Elsevier. A1R=adenosine receptor type 1. ADO=adenosine. Akt=a serine/threonine kinase family. BDNF=brain-derived neurotrophic factor. CRE=cyclic AMP response element. EAAT=excitatory amino-acid transporter. EPO=erythropoeitin. ERK=extracellular signal-regulated kinase. FGF2=fibroblast growth factor 2. GDNF=glia-derived growth factor. GluR2=glutamate receptor subunit 2. GLT=glutamate transporter. HIF=hypoxia-inducible factor. HK2=hexokinase 2. HSP=heat shock protein. IEG=immediate early gene. IGF1=insulin-like growth factor 1. IL=interleukin. IL1RA=interleukin 1 receptor antagonist. JAK=janus kinase. JNK=c-Jun N-terminal kinase. K_ATP=ATP-sensitive potassium channel. MAPK=mitogen-activated protein kinase. NALP=NACHT-containing, LRR-containing, and pyrin-domain-containing protein. NFκB=nuclear factor κB. NGF=nerve growth factor. NMDAR=NMDA receptor. NO=nitric oxide. NOS= nitric oxide synthase. OFR=oxygen free radicals. PDGFA=platelet-derived growth factor receptor A. PI3K=phosphoinositide-3 kinase. PKB=protein kinase B. PKC=protein kinase C. STAT=signal transducer and activator of transcription.TNF=tumour necrosis factor. TLR=Toll-like receptor. TRAF=TNF receptor-associated factor. VEGF=vascular endothelial growth factor.