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Neuroprotective mechanisms of hypothermia in brain ischaemia

Nature Reviews Neuroscience volume 13, pages 267–278 (2012)Cite this article

Subjects

Key Points

  • Small decreases in temperature can have remarkable effects on protecting the brain from ischaemic insults.

  • The mechanisms are multi-faceted, but span the spectrum of preserving cell metabolism, suppressing inflammation, increasing growth factor expression and favourably allowing regeneration and repair of the injured brain.

  • MicroRNAs and other temperature-sensitive RNAs may orchestrate the complex molecular events by selectively affecting gene expression to favour brain protection.

  • Therapeutic cooling can prevent complications of brain ischaemia such as oedema formation and brain haemorrhage.

  • Large prospective clinical studies have now demonstrated improvement in neurological outcome in some conditions of ischaemic brain injury.

  • Ongoing research continues to refine how therapeutic cooling may be delivered at the clinical level, including optimizing cooling conditions, studying related disease states and pharmacologic approaches.

Abstract

Cooling can reduce primary injury and prevent secondary injury to the brain after insults in certain clinical settings and in animal models of brain insult. The mechanisms that underlie the protective effects of cooling — also known as therapeutic hypothermia — are slowly beginning to be understood. Hypothermia influences multiple aspects of brain physiology in the acute, subacute and chronic stages of ischaemia. It affects pathways leading to excitotoxicity, apoptosis, inflammation and free radical production, as well as blood flow, metabolism and blood–brain barrier integrity. Hypothermia may also influence neurogenesis, gliogenesis and angiogenesis after injury. It is likely that no single factor can explain the neuroprotection provided by hypothermia, but understanding its myriad effects may shed light on important neuroprotective mechanisms.

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Figure 1: The events involved in the pathogenesis of cerebral ischaemia are classified by their active time.
Figure 2: Apoptotic pathways.
Figure 3: Effects of therapeutic hypothermia on the pathogenesis of cerebral ischaemia.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (NS40516 to M.Y.), the Veteran's Merit Award (M.Y.), the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A100870 to H.S.H.) and the Industrial Strategic technology development program (10035197 to H.S.H.), which is funded by the Ministry of Knowledge Economy (MKE), Korea. Grants to M.Y. were administered by the Northern California Institute for Research and Education, and supported by resources of the Veterans Affairs Medical Center, San Francisco, California.

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Authors and Affiliations

  1. Department of Neurology, University of California, San Francisco, 94143-0248, California, USA

    Midori A. Yenari

  2. San Francisco Veterans Affairs Medical Center, San Francisco, 94121, California, USA

    Midori A. Yenari

  3. Department of Physiology, Kyungpook National University School of Medicine, Daegu, 700-422, South Korea

    Hyung Soo Han

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  1. Midori A. Yenari
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Correspondence to Midori A. Yenari.

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Glossary

Apoptosis

Innate, programmed cell death that is energy-dependent and leads to nuclear and cytoplasmic compaction with characteristic blebbing of the nucleus. It occurs during development but also in disease states.

Necrosis

Acute, uncontrolled cell death that leads to cell lysis.

Reperfusion

The period of resumed blood flow to the tissue after arterial occlusion.

Hyperaemia

Higher than normal blood flow.

Torpor

A prolonged state of energy conservation that allows heterothermic animals to tolerate limitations in resource availability that are encountered in extreme environments.

Nestin

An intermediate filament protein used as a marker for CNS stem cells.

Coagulopathies

Abnormal conditions of blood clotting or blood clot lysis.

Autophagy

The breakdown of a cell's own components by the lysosome.

Anoikis

A form of programmed cell death that is activated when cells detach from the extracellular matrix

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Yenari, M., Han, H. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13, 267–278 (2012). https://doi.org/10.1038/nrn3174

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