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- Title
A working model for hypothermic neuroprotection.
- Authors
Wassink, Guido; Davidson, Joanne O.; Lear, Christopher A.; Juul, Sandra E.; Northington, Frances; Bennet, Laura; Gunn, Alistair J.
- Abstract
Therapeutic hypothermia significantly improves survival without disability in near‐term and full‐term newborns with moderate to severe hypoxic–ischaemic encephalopathy. However, hypothermic neuroprotection is incomplete. The challenge now is to find ways to further improve outcomes. One major limitation to progress is that the specific mechanisms of hypothermia are only partly understood. Evidence supports the concept that therapeutic cooling suppresses multiple extracellular death signals, including intracellular pathways of apoptotic and necrotic cell death and inappropriate microglial activation. Thus, the optimal depth of induced hypothermia is that which effectively suppresses the cell death pathways after hypoxia–ischaemia, but without inhibiting recovery of the cellular environment. Thus mild hypothermia needs to be continued until the cell environment has recovered until it can actively support cell survival. This review highlights that key survival cues likely include the inter‐related restoration of neuronal activity and growth factor release. This working model suggests that interventions that target overlapping mechanisms, such as anticonvulsants, are unlikely to materially augment hypothermic neuroprotection. We suggest that further improvements are most likely to be achieved with late interventions that maximise restoration of the normal cell environment after therapeutic hypothermia, such as recombinant human erythropoietin or stem cell therapy. The progressive phases of perinatal brain damage after severe hypoxia–ischaemia, and how interventions (i.e. hypothermia, recombinant human erythropoietin (rEpo) and stem cells) interact with deleterious processes induced in these phases. Therapeutic cooling is effective at suppressing damaging mechanisms in the latent and second phases, including inflammation and withdrawal of trophic factors, which helps stabilise neural mitochondria and so provides neuroprotection. This hypothermia‐induced suppression should be continued until cellular homeostasis and prosurvival signalling (e.g. growth factor and electroencephalogram (EEG) restoration) have recovered. Future research should focus on preclinical treatments that further support these survival cues and suppress long‐lasting injurious processes (i.e. persistent inflammation and epigenetic changes) in the third phase. rEpo and stem cells are promising candidates.
- Subjects
THERAPEUTIC hypothermia; GROWTH factors; ERYTHROPOIETIN; STEM cell treatment; BRAIN damage
- Publication
Journal of Physiology, 2018, Vol 596, Issue 23, p5641
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/JP274928