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

doi:10.1016/S1474-4422(09)70054-7

The Lancet Neurology

Volume 8, Issue 4, April 2009, Pages 398-412

https://doi.org/10.1016/S1474-4422(09)70054-7 Get rights and content

Summary

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.

Introduction

Organisms have evolved mechanisms to protect against tissue damage and to compensate (or even regenerate) in the event of injury. The two most elementary challenges, and thus the greatest evolutionary pressures, for living organisms are infection and deprivation of substrate or energy. Pathophysiological research has focused on mechanisms by which tissue is damaged by noxious stimuli or processes and how to prevent this injury.

To identify endogenous mechanisms of protection and repair, and to make use of these mechanisms therapeutically, biomedical investigators have developed preconditioning strategies. Preconditioning is a procedure by which a noxious stimulus near to but below the threshold of damage is applied to the tissue. Shortly after preconditioning or after a delay, the organ (and therefore the organism) develops resistance to, or tolerance of, the same, similar, or even different noxious stimuli given beyond the threshold of damage. Preconditioning thereby protects against subsequent injury.

Ischaemic brain injuries, resulting either from global or focal decreases in perfusion, are among the most common and important causes of disability and death worldwide. The consequences of global cerebral ischaemia after cardiac arrest (and successful resuscitation), focal occlusions or disruption of brain vessels (ie, stroke, including subarachnoid haemorrhage and intraparenchymatous haemorrhage), and ischaemic brain damage after cardiac or brain surgery affect many millions of people in the USA alone.1, 2 Research into preconditioning aims at developing new therapeutic approaches to benefit these patients. On the one hand, preconditioning is an attractive experimental strategy to identify endogenous protective or regenerative mechanisms that can be therapeutically induced or supplemented. On the other hand, preconditioning could be used as a therapeutic technique by inducing tolerance in individuals in whom ischaemic events are anticipated, such as high-risk surgical cohorts or patients with subarachnoid haemorrhage or transient ischaemic attack. Many articles have reviewed various features of ischaemic preconditioning, tolerance, and endogenous neuroprotection in the brain.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 In this Review, we give a brief overview of preconditioning, including ischaemic preconditioning, and its clinical potential and discuss the therapeutic exploitation of endogenous neuroprotection. Additionally, we hope to expand the neurocentric view of preconditioning and tolerance held by neuroscientists and neurologists to include the immune system.

Section snippets

Induction of ischaemic tolerance

Many pathological pathways converge on shared pathways of cell injury, death, and repair. For example, although the causes of acute neurodegeneration (eg, stroke) and chronic neurodegeneration (eg, Parkinson's disease) are different, the mechanisms of cell injury—including excitotoxicity, inflammation, and apoptosis—overlap,¹⁹ as do the pathways of survival and regeneration. Therefore, the options for inducing preconditioning and tolerance are not specific to the type of injury, which is

Genomic reprogramming

The induction of ischaemic tolerance is accompanied by substantial change in gene expression, suggesting that preconditioning stimulates a fundamental genomic reprogramming of cells that confers cytoprotection and survival.⁶ The genomic response after ischaemic preconditioning is a signature of the complex interplay of multiple signalling pathways. These highly specialised pathways in different cell types of the brain seem to refine the cellular and systemic response to combat the noxious

Hypoxia-inducible factor: a regulator of ischaemic preconditioning?

One of the key regulators of the genomic response after ischaemic preconditioning is the transcriptional activator hypoxia-inducible factor (HIF). This protein is a heterodimer with an unstable α-subunit (HIFα) and a stable β-subunit (HIFβ).⁶⁴ HIF is regulated by an evolutionarily conserved pathway mediated by oxygen-dependent post-translational hydroxylation of HIFα. Under typical oxygen conditions, HIFα becomes hydroxylated at two prolyl residues by members of the prolyl-4 hydroxylase domain

Improving outcome after stroke

The endogenous response aimed at improving outcome after decreased substrate delivery to the brain (ie, ischaemia), which is at least partly mediated by HIF, relies on four basic actions: increased substrate delivery, decreased energy use, antagonised mechanisms of damage, and improved recovery. Preconditioning can modulate all four of these actions.

Immunological tolerance

Activation of the innate immune response is a consequence of stroke, and preclinical data indicate that inflammation in the immediate post-stroke period contributes to ischaemic brain injury.¹⁶² Clinical data attribute a detrimental role to post-stroke inflammation. The most convincing of these data came from a trial aimed at preventing leucocyte influx into ischaemic brain tissue. The protein used in this trial, however, induced a systemic inflammatory response associated with worse outcome.¹⁶³

Clinical use of preconditioning

Preconditioning has been successful as an experimental procedure to identify mechanisms for brain protection and regeneration. Important examples of strategies to modulate these mechanisms include erythropoietin, activators of mitochondrial K_ATP channels, and volatile anaesthetics.

Because of the high risk of neurological complications associated with coronary artery bypass grafting and carotid endarterectomy, patients scheduled for these procedures could potentially benefit from therapeutic

Clinical use: challenges and opportunities

A central belief in preconditioning research is that the preconditioning stimulus must be sub-threshold and should not cause damage. The postulated dose response of the preconditioning stimulus therefore ranges from no response at low intensities to the protected state at higher intensities; a further increase in stimulus intensity will cause overt damage. The therapeutic range of preconditioning is narrow.4, 71 Most preconditioning studies are short in duration, with limited periods of

Conclusions

Preconditioning (ie, induced tolerance) is an experimental technique in which protective and regenerative mechanisms of the brain can be isolated from deleterious mechanisms. The molecular signalling cascades of endogenous brain protection—from stimulus and sensor to transducers and effectors—are being identified (figure 2). Research has led to the discovery of several promising strategies for the treatment of patients with acute CNS injury. Additionally, studies of preconditioning have led to

Search strategy and selection criteria

References for this Review were identified through searches of PubMed by use of search terms that included “preconditioning”, “ischemic tolerance”, “neuroprotection”, “brain repair”, “brain ischemia”, “brain hypoxia”, and “stroke” (“tolerance” and “preconditioning” were common modifiers), with various search periods (from January, 1980, to December, 2008). The full list of search terms is available from the author on request. The bibliographies of the most recent articles were also

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Isoflurane preconditioning induced genomic changes in mouse cortex
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Altered patterns of genetic expression induced by isoflurane preconditioning in mouse brain have not yet been investigated. The aim of our pilot study is to examine the temporal sequence of changes in the transcriptome of mouse brain cortex produced by isoflurane preconditioning.
Twelve-wk-old wild-type (C57BL/6J) male mice were randomly assigned for the experiments. Mice were exposed to isoflurane 2% in air for 1 h and brains were harvested at the following time points—immediately (0 h), and at 6, 12, 24, 36, 48, and 72 h after isoflurane exposure. A separate cohort of mice were exposed to three doses of isoflurane on days 1, 2, and 3 and brains were harvested after the third exposure. The NanoString mouse neuropathology panel was used to analyse isoflurane-induced gene expression in the cortex. The neuropathology panel included 760 genes covering pathways involved in neurodegeneration and other nervous system diseases, and 10 internal reference genes for data normalisation.
Genes involving several pathways were upregulated and downregulated by isoflurane preconditioning. Interestingly, a biphasic response was noted, meaning, an early expression of genes (until 6 h), followed by a transient pause (until 24 h), and a second wave of genomic response beginning at 36 h of isoflurane exposure was noted.
Isoflurane preconditioning induces significant alterations in the genes involved in neurodegeneration and other nervous system disorders in a temporal sequence. These data could aid in the identification of molecular mechanisms behind isoflurane preconditioning-induced neuroprotection in various central nervous system diseases.
Research hotspots and frontiers of preconditioning in cerebral ischemia: A bibliometric analysis
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Preconditioning is a promising strategy against ischemic brain injury, and numerous studies in vitro and in vivo have demonstrated its neuroprotective effects. However, at present there is no bibliometric analysis of preconditioning in cerebral ischemia. Therefore, a comprehensive overview of the current status, hot spots, and emerging trends in this research field is necessary.
Studies on preconditioning in cerebral ischemia from January 1999–December 2022 were retrieved from the Web of Science Core Collection (WOSCC) database. CiteSpace was used for data mining and visual analysis.
A total of 1738 papers on preconditioning in cerebral ischemia were included in the study. The annual publications showed an upwards and then downwards trend but currently remain high in terms of annual publications. The US was the leading country, followed by China, the most active country in recent years. Capital Medical University published the largest number of articles. Perez-Pinzon, Miguel A contributed the most publications, while KITAGAWA K was the most cited author. The focus of the study covered three areas: (1) relevant diseases and experimental models, (2) types of preconditioning and stimuli, and (3) mechanisms of ischemic tolerance. Remote ischemic preconditioning, preconditioning of mesenchymal stem cells (MSCs), and inflammation are the frontiers of research in this field.
Our study provides a visual and scientific overview of research on preconditioning in cerebral ischemia, providing valuable information and new directions for researchers.
Plasma metabolomic profiling of patients with transient ischemic attack reveals positive role of neutrophils in ischemic tolerance
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Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of patients with stroke. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of patients with TIA for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke.
Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse middle cerebral artery occlusion (MCAO)-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of patients with TIA were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance.
Plasma metabolomics analysis identified five differentially upregulated metabolites associated with potentially TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in patients with TIA that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted.
TIA-induced potential ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.
National Natural Science Foundation of China (81974210), Science and Technology Planning Project of Guangdong Province, China (2020A0505100045), Natural Science Foundation of Guangdong Province (2019A1515010671), Science and Technology Program of Guangzhou, China (2023A03J0577), and Natural Science Foundation of Jiangxi, China（20224BAB216043).
The association between sleep spindles and cognitive function in middle-aged and older men from a community-based cohort study
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Previous studies examining associations between sleep spindles and cognitive function attempted to account for obstructive sleep apnea without consideration for potential moderating effects. To elucidate associations between sleep spindles, cognitive function, and obstructive sleep apnea, this study of community-dwelling men examined cross-sectional associations between sleep spindle metrics and daytime cognitive function outcomes following adjustment for obstructive sleep apnea and potential obstructive sleep apnea moderating effects.
Florey Adelaide Male Ageing Study participants (n = 477, 41-87 years) reporting no previous obstructive sleep apnea diagnosis underwent home-based polysomnography (2010-2011). Cognitive testing (2007-2010) included the inspection time task (processing speed), trail-making tests A (TMT-A) (visual attention) and B (trail-making test-B) (executive function), and Fuld object memory evaluation (episodic memory). Frontal spindle metrics (F4-M1) included occurrence (count), average frequency (Hz), amplitude (µV), and overall (11-16 Hz), slow (11-13 Hz), and fast (13-16 Hz) spindle density (number/minute during N2 and N3 sleep).
In fully adjusted linear regression models, lower N2 sleep spindle occurrence was associated with longer inspection times (milliseconds) (B = −0.43, 95% confidence interval [−0.74, −0.12], p = .006), whereas higher N3 sleep fast spindle density was associated with worse TMT-B performance (seconds) (B = 18.4, 95% confidence interval [1.62, 35.2], p = .032). Effect moderator analysis revealed that in men with severe obstructive sleep apnea (apnea-hypopnea index ≥30/hour), slower N2 sleep spindle frequency was associated with worse TMT-A performance (χ² = 12.5, p = .006).
Specific sleep spindle metrics were associated with cognitive function, and obstructive sleep apnea severity moderated these associations. These observations support the utility of sleep spindles as useful cognitive function markers in obstructive sleep apnea, which warrants further longitudinal investigation.
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This paired case-control study aimed to evaluate the efficacy and safety of remote ischemic conditioning (RIC) in patients with acute cerebral infarction (CI) and explore potential serological markers of RIC.
Patients with acute CI (<72 h) were matched 1:1 according to age, sex, and CI conditions and were divided into the RIC group and the control group. The RIC group received RIC intervention for 7 days on top of routine treatment, while the control group received a sham RIC. The curative effects and adverse reactions were observed.
A total of 66 patients (mean age 60.00 ± 11.37 years; mean time of acute CI onset 32.91 ± 17.94 h) completed the study. The National Institute of Health stroke scale score on day 7, modified Rankin Scale scores on day 7 and day 90 were significantly lower than the baseline in the RIC group (P < 0.001, P = 0.003, P = 0.004, respectively) but not in the control group (P = 0.056, P = 0.169, P = 0.058, respectively). RIC was well-tolerated, and no adverse events were reported. Both plasma hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor increased in the RIC group from day 0 to day 7, while they decreased in the control group. The changes in plasma HIF-1α in the RIC group were statistically different from those in the control group (P = 0.006).
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Volatile sedation after aneurysmal subarachnoid hemorrhage (aSAH) promises several advantages, but there are still concerns regarding intracranial hypertension due to vasodilatory effects. We prospectively analyzed cerebral parameters during the switch from intravenous to volatile sedation with isoflurane in patients with poor-grade (World Federation of Neurosurgical Societies grade 4–5) aSAH.
Eleven patients were included in this prospective observational study. Between day 3 and 5 after admission, intravenous sedation was switched to isoflurane using the Sedaconda Anesthetic Conserving Device (Sedana Medical, Danderyd, Sweden). Intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygenation (PBrO₂), cerebral mean flow velocities (MFVs; transcranial Doppler ultrasound) and regional cerebral oxygen saturation (rSO₂, near-infrared spectroscopy monitoring), as well as cardiopulmonary parameters were assessed before and after the sedation switch (–12 to +12 hours). Additionally, perfusion computed tomography data during intravenous and volatile sedation were analyzed retrospectively for changes in cerebral blood flow.
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ReviewPreconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use

Summary

Introduction

Section snippets

Induction of ischaemic tolerance

Genomic reprogramming

Hypoxia-inducible factor: a regulator of ischaemic preconditioning?

Improving outcome after stroke

Immunological tolerance

Clinical use of preconditioning

Clinical use: challenges and opportunities

Conclusions

Search strategy and selection criteria

Neuropharmacology

Trends Neurosci

Comp Biochem Physiol A Mol Integr Physiol

Trends Pharmacol Sci

Trends Neurosci

Neuroscience

Neurosci Lett

Lancet

J Surg Res

Brain Res

Neurosci Lett

Life Sci

Curr Opin Pharmacol

J Biol Chem

Lancet

Neurobiol Dis

Exp Neurol

Mol Cell

Neurosci Lett

Am J Pathol

J Biol Chem

Cell

J Biol Chem

Exp Neurol

Neuroscience

The current neurologic burden of illness and injury in the United States

Neurology

How common are the “common” neurologic disorders?

Neurology

Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning

Glia

Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis

Stroke

Toll-like receptors and tolerance to ischaemic injury in the brain

Biochem Soc Trans

Cerebral preconditioning and ischaemic tolerance

Nat Rev Neurosci

Inhibition of toll-like receptor and cytokine signaling–a unifying theme in ischemic tolerance

J Cerebr Blood Flow Metab

Endogenous mechanisms of neuroprotection

Epilepsia

Molecular physiology of preconditioning-induced brain tolerance to ischemia

Physiol Rev

Role of reactive oxygen species and protein kinase C in ischemic tolerance in the brain

Antiox Redox Signal

Killer proteases and little strokes–how the things that do not kill you make you stronger

J Cerebr Blood Flow Metabol

Hypoxia preconditioning in the brain

Develop Neurosci

Ischemic tolerance

J Cerebr Blood Flow Metabol

Mining for survival genes

Biochem Soc Trans

The development of resistance by rats and guinea pigs to amounts of trauma usually fatal

Am J Physiol

Alterations in lysosomes (intracellular enzymes) during shock; effects of preconditioning (tolerance) and protective drugs

Int Anesthesiol Clinics

Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit

Circulation

Remote ischaemic preconditioning: underlying mechanisms and clinical application

Cardiovasc Res

Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia

Arterioscler Thrombosis Vasc Biol

Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial

Circulation

Myocardial gene reprogramming associated with a cardiac cross-resistant state induced by LPS preconditioning

Am J Physiol

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