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Brain vulnerability and viability after ischaemia

Nature Reviews Neuroscience volume 22, pages 553–572 (2021)Cite this article

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Abstract

The susceptibility of the brain to ischaemic injury dramatically limits its viability following interruptions in blood flow. However, data from studies of dissociated cells, tissue specimens, isolated organs and whole bodies have brought into question the temporal limits within which the brain is capable of tolerating prolonged circulatory arrest. This Review assesses cell type-specific mechanisms of global cerebral ischaemia, and examines the circumstances in which the brain exhibits heightened resilience to injury. We suggest strategies for expanding such discoveries to fuel translational research into novel cytoprotective therapies, and describe emerging technologies and experimental concepts. By doing so, we propose a new multimodal framework to investigate brain resuscitation following extended periods of circulatory arrest.

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Fig. 1: Cerebral microvasculature structure, function and dysfunction.
Fig. 2: Excitatory neurotransmission and glutamate-mediated excitotoxicity.
Fig. 3: Neuron–microglial cell interplay and pro-inflammatory signalling.
Fig. 4: Mitochondrial function and dysfunction during ischaemia–reperfusion injury.
Fig. 5: A combined therapeutic strategy for reducing global ischaemic injury.

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Authors and Affiliations

  1. Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Stefano G. Daniele, Zvonimir Vrselja, David Andrijevic & Nenad Sestan

  2. Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Stefano G. Daniele, Zvonimir Vrselja, David Andrijevic & Nenad Sestan

  3. Medical Scientist Training Program (MD-PhD), Yale School of Medicine, New Haven, CT, USA

    Stefano G. Daniele

  4. Department of Cardiovascular Surgery, University Hospital Freiburg, Medical Faculty of the Albert-Ludwigs-University Freiburg, Freiburg, Germany

    Georg Trummer, Christoph Benk, Domagoj Damjanovic, Jan-Steffen Pooth & Friedhelm Beyersdorf

  5. Max Planck Institute for Metabolism Research, Cologne, Germany

    Konstantin A. Hossmann

  6. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA

    Kevin T. Gobeske

  7. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    David Dellal

  8. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    Nenad Sestan

  9. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    Nenad Sestan

  10. Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA

    Nenad Sestan

  11. Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT, USA

    Nenad Sestan

  12. Yale Child Study Center, New Haven, CT, USA

    Nenad Sestan

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Contributions

S.G.D., G.T., K.A.H., Z.V., K.T.G., F.B. and N.S. researched data for the article. S.G.D., G.T., K.A.H., F.B. and N.S. wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Friedhelm Beyersdorf or Nenad Sestan.

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Competing interests

S.G.D., Z.V. and N.S. are listed with J. Silbereis as inventors on a patent held by Yale University entitled “Methods, systems and compositions for normothermic ex vivo restoration and preservation of intact organs” (WO2019157277A1). F.B., C.B., and G.T. are shareholders in Resuscitec GmbH, a company originating from the University of Freiburg. K.A.H., K.T.G., D.A., D. Damjanovic, J-S.P. and D. Dellal declare no competing interests.

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Glossary

Delayed neuronal death

Morphological and histological features associated with neuronal cell damage and death that become apparent multiple days following an injury or insult.

Rational polytherapy

Combination therapy that is rationally designed to target multiple deleterious mechanisms simultaneously or in a deliberate sequence.

Extracorporeal perfusion

The use of a mechanical pump device with auxiliary components that circulates either a patient’s blood or a specialized solution to provide circulatory support.

Electroencephalogram flattening

The absence of synchronous electrical activity in the brain, also known as a flat line or isoelectric reading.

Acidosis

The condition in which cellular or tissue pH decreases below the normal homeostatic range owing to the accumulation of protons.

Anoxic depolarization

An acute neuronal event involving the loss of cell membrane potentials caused by energy failure secondary to oxygen deprivation.

‘No-reflow’ phenomenon

The persistence of microvascular perfusion deficits despite the successful re-establishment of global circulation following ischaemia.

Haemodilution

The act of reducing the concentration of cells and components in the blood through the introduction of a fluid.

Erythrocyte

A red blood cell.

Haemoconcentration

The process of concentrating cells and components in the blood through the removal of fluid.

Neurovascular unit

A specialized functional and structural unit in the brain composed of endothelial, glial and neuronal cells that facilitate coupling between neuronal activity and blood flow.

Blood–brain barrier

(BBB). A specialized barrier within the vasculature of the brain that limits the non-selective movement of peripheral blood components into the brain.

Glycocalyx

A network of biomolecules that line the luminal surface of the cerebrovascular endothelium.

Weibel–Palade bodies

Storage granules in endothelial cells that contain multiple biomolecules, such as P-selectin.

Excitotoxicity

A pathological process by which neurons are damaged and killed through the overactivation of cellular receptors by the excitatory neurotransmitter glutamate.

Simulated in vitro ischaemia

An experimental method through which cultured cells and tissues are subjected to conditions similar to in vivo ischaemia by the combination of hypoxia and hypoglycaemia.

Necrosis

A form of cell death that results from unregulated digestion or autolysis of the cell.

Reverse electron transfer

The process by which electrons are transferred in the reverse order in the electron transport chain, leading to the reduction of NAD+.

Non-shockable

Describing cardiac rhythms that are incompatible with electrical defibrillation, such as pulseless electrical activity and asystole.

Proximal occlusions

Clots or blockages in the proximal parts of large vessels (for example, of the neck or base of the brain).

Perfluorocarbon

A class of organic molecules that form the basis of solvents with high oxygen-carrying capacities.

Histotoxic hypoxia

A chemically induced form of hypoxia in which cells are unable to utilize oxygen despite adequate delivery or concentration of oxygen.

Ventricular fibrillation

An abnormal cardiac rhythm in which the ventricles display erratic and uncoordinated contractions (fibrillation) owing to aberrant electrical conduction.

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Daniele, S.G., Trummer, G., Hossmann, K.A. et al. Brain vulnerability and viability after ischaemia. Nat Rev Neurosci 22, 553–572 (2021). https://doi.org/10.1038/s41583-021-00488-y

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