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.

Download full-text


Available from: Midori A Yenari, Jan 20, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    04/2015; 6(6). DOI:10.1016/j.ebiom.2015.04.004
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Cellular Neuroscience 12/2014; 8. DOI:10.3389/fncel.2014.00416 · 4.29 Impact Factor
  • Source
    • "Some depression is likely to result from the Q 10 effect of the up to 3–4°C drop in brain temperature that has been documented in harp seals (Pagophilus groenlandicus) and hooded seals during simulated diving (Fig. 8) (Blix et al., 2010; Odden et al., 1999). Such brain cooling probably also protects neurons by limiting both primary and secondary injury through its other known effects on metabolic, molecular and cellular events (Yenari and Han, 2012). Also, data from harbor seals (Phoca vitulina) that were subjected to simulated dives in the laboratory suggest that cerebral O 2 uptake does decrease towards the end of long dives, but a simultaneous rise in lactate release implies that this drop – at least in part – reflects insufficient oxygen supply, rather than metabolic depression (Kerem and Elsner, 1973). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxia-tolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy.
    Journal of Experimental Biology 04/2014; 217(Pt 7):1024-39. DOI:10.1242/jeb.085381 · 2.90 Impact Factor
Show more