Article

Neuroprotective mechanisms of hypothermia in brain ischaemia.

Department of Neurology, University of California, San Francisco, California 94143-0248, USA.
Nature Reviews Neuroscience 02/2012; 13(4):267-78. DOI: 10.1038/nrn3174
Source: PubMed

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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    ABSTRACT: a r t i c l e i n f o Hypothermia is potently neuroprotective but poor mechanistic understanding has restricted its clinical use. Rodent studies indicate that hypothermia can elicit preconditioning, wherein a subtoxic cellular stress confers resistance to an otherwise lethal injury. The molecular basis of this preconditioning remains obscure. Here we explore molecular effects of cooling using functional cortical neurons differentiated from human pluripotent stem cells (hCNs). Mild-to-moderate hypothermia (28–32 °C) induces cold-shock protein expression and mild endoplasmic reticulum (ER) stress in hCNs, with full activation of the unfolded protein response (UPR). Chemical block of a principal UPR pathway mitigates the protective effect of cooling against oxidative stress, whilst pre-cooling neurons abrogates the toxic injury produced by the ER stressor tunicamycin. Cold-stress thus preconditions neurons by upregulating adaptive chaperone-driven pathways of the UPR in a manner that precipitates ER-hormesis. Our findings establish a novel arm of neurocryobiology that could reveal multiple therapeutic targets for acute and chronic neuronal injury.

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Midori A Yenari