Yenari MA, Han HSNeuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267-278

Department of Neurology, University of California, San Francisco, California 94143-0248, USA.
Nature Reviews Neuroscience (Impact Factor: 31.43). 02/2012; 13(4):267-78. DOI: 10.1038/nrn3174
Source: PubMed


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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Available from: Midori A Yenari, Jan 20, 2015
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    • "Overall we have demonstrated that hypothermia protects human cortical neurons in vitro from glutamate-mediated excitotoxicity, in addition to oxidative stress (Rzechorzek et al., 2015) – key components of both acute and chronic neuronal injury. The molecular mechanisms underlying hypothermic neuroprotection are ill-defined, although several pathways are implicated in other model systems and within the cyclical adaptation of hibernating brains (Arendt et al., 2003; Stieler et al., 2011; Yenari and Han, 2012; Peretti et al., 2015; Zhu et al., 2015). Direct effects such as a reduced rate of generation of oxidative species and changes in glutamate receptor function may be involved in hypothermic neuroprotection against oxidative and excitotoxic stress respectively (Dietrich et al., 2009). "
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    ABSTRACT: Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling — conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients.
    Full-text · Article · Dec 2015 · EBioMedicine
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    • "Hypothermia was induced at 5 w when N90% of hCNs are functional (Bilican et al., 2014; Livesey et al., 2014). Identical plates were cultured at 28, 32 or 37 °C to simulate 'moderate hypothermia', 'mild hypothermia' or 'normothermia', respectively (Yenari and Han, 2012). Samples for transcript analysis were lifted at 3 and 24 h, after which additional samples were processed for immunocytochemistry and biochemistry. "
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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.
    Full-text · Article · Apr 2015 · EBioMedicine
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    • "Such changes include Abbreviations: SUMO, small ubiquitin-related modifier; OGD, oxygenglucose deprivation; ROG, recovery from oxygen/glucose deprivation; Ubc9, ubiquitin conjugase 9; Tg, transgenic; pMCAO, permanent middle cerebral artery occlusion. reductions in metabolic and enzymatic activity, glutamate release and re-uptake, inflammation, the production of reactive oxygen species, and expression of various genes (reviewed in González- Ibarra et al., 2011; Yenari and Han, 2012). Preliminary clinical studies utilizing mild to moderate hypothermia as a treatment for acute ischemic stroke are ongoing and results obtained thus far have been encouraging (Macleod et al., 2010; van der Worp et al., 2010; Abdullah and Husin, 2011; Kollmar et al., 2012). "
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    ABSTRACT: The molecular mechanisms underlying hypothermic neuroprotection have yet to be fully elucidated. Herein we demonstrate that global SUMOylation, a form of post-translational modification with the Small Ubiquitin-like MOdifer, participates in the multimodal molecular induction of hypothermia-induced ischemic tolerance. Mild (32 • C) to moderate (28 • C) hypothermic treatment(s) during OGD (oxygen-glucose-deprivation) or ROG (restoration of oxygen/glucose) increased global SUMO-conjugation levels and protected cells (both SHSY5Y and E18 rat cortical neurons) from OGD and ROG-induced cell death. Hypothermic exposure either before or after permanent middle cerebral artery occlusion (pMCAO) surgery in wild type mice increased global SUMO-conjugation levels in the brain and in so doing protected these animals from pMCAO-induced ischemic damage. Of note, hypothermic exposure did not provide an additional increase in protection from pMCAO-induced ischemic brain damage in Ubc9 transgenic (Ubc9 Tg) mice, which overexpress the sole E2 SUMO conjugating enzyme and thereby display elevated basal levels of global SUMOylation under normothermic conditions. Such evidence suggests that increases in global SUMOylation are critical and may account for a substantial part of the observed increase in cellular tolerance to brain ischemia caused via hypothermia.
    Full-text · Article · Dec 2014 · Frontiers in Cellular Neuroscience
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