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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When incubated at 4 degrees C, cultured rat hepatocytes or liver endothelial cells exhibit pronounced injury and, during earlier rewarming, marked apoptosis. Both processes are mediated by reactive oxygen species, and marked protective effects of iron chelators as well as the protection provided by various other antioxidants suggest that hydroxyl radicals, formed by classical Fenton chemistry, are involved. However, when we measured the Fenton chemistry educt hydrogen peroxide and its precursor, the superoxide anion radical, formation of both had markedly decreased and steady-state levels of hydrogen peroxide did not alter during cold incubation of either liver endothelial cells or hepatocytes. Similarly, there was no evidence of an increase in O2-/H2O2 release contributing to cold-induced apoptosis occurring on rewarming. In contrast to the release/level of O2- and H2O2, cellular homeostasis of the transition metal iron is likely to play a key role during cold incubation of cultured hepatocytes: the hepatocellular pool of chelatable iron, measured on a single-cell level using laser scanning microscopy and the fluorescent indicator phen green, increased from 3.1 +/- 2.3 microM (before cold incubation) to 7.7 +/- 2.4 microM within 90 min after initiation of cold incubation. This increase in the cellular chelatable iron pool was reversible on rewarming after short periods of cold incubation. The cold-induced increase in the hepatocellular chelatable iron pool was confirmed using the calcein method. These data suggest that free radical-mediated hypothermia injury/cold-induced apoptosis is primarily evoked by alterations in the cellular iron homeostasis/a rapid increase in the cellular chelatable iron pool and not by increased formation of O2-/H2O2.
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PMID:Hypothermia injury/cold-induced apoptosis--evidence of an increase in chelatable iron causing oxidative injury in spite of low O2-/H2O2 formation. 1102 79

Oxidative stress is one of the major causes of cellular injury. Various reactive oxygen (ROS) and nitrogen (RNS) species such as superoxide, hydroxyl radical, peroxynitrite, and nitric oxide are involved in the manifestations of different types of organ toxicity and the resultant syndromes, symptoms, or diseases. Hypothermic conditions have been reported to reduce the oxidative stress in various in vitro and in vivo studies. In the present study, we sought to determine the effect of lowered temperatures on oxidative stress-induced cell death in Chinese hamster ovary (CHO) cells. We also investigated the oxidative stress-induced alterations in the expression of anti-apoptotic protein, bcl-2, in CHO cells at lowered temperatures. CHO cells were incubated at four different temperatures of 30, 32, 35, and 37 degrees C (control temperature) from 1 to 4 d. In another set, the cells were incubated with 100 microM hydrogen peroxide (H(2)O(2)) for 30 min before harvesting at different time points. The cells were harvested at 1, 2, 3, and 4 d. Cell survival was significantly higher at 30 degrees C as compared to 37 degrees C over 4 d of incubation. In cells incubated with H(2)O(2), significantly higher cell viability was observed at lower temperatures as compared to the cells incubated at 37 degrees C. The activity of glutathione peroxidase (GSH-Px) also increased significantly at lower temperatures. Lowered temperature also provided a significant increase in the expression of anti-apoptotic protein, bcl-2 after 4 d of incubation. These data suggest that hypothermic conditions lowers the risk of oxidative stress-induced cellular damage and programmed cell death by increasing the activity of GSH-Px and by the induction in the expression of the anti-apoptotic protein, bcl-2.
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PMID:Hypothermia enhances bcl-2 expression and protects against oxidative stress-induced cell death in Chinese hamster ovary cells. 1146 79

Mild hypothermia is a well-known method of reducing brain damage caused by traumatic, hypoxic, and ischemic injury. To elucidate the neuroprotective mechanism induced by hypothermic treatment, we compared gene expression profiles in the hippocampus of gerbils rendered ischemic for 15 min and then reperfused for 3 h under conditions of normothermia (37+/-0.5 degrees C) or hypothermic treatment (34+/-0.5 degrees C). Using the differential display method, we observed significantly reduced expression of the 78 kDa glucose regulated protein (GRP78), in ischemic gerbil hippocampus that underwent normothermic reperfusion, but normal GRP78 expression in animals that underwent hypothermic reperfusion. In situ hybridization and Northern blot analysis showed GRP78 mRNA expression was reduced in the CA1 region of the hippocampus under normothermic conditions, but was not reduced under hypothermic conditions. Western blot analysis also showed the levels of immunoreactive GRP78 protein decreased in neurons of the hippocampal CA-1 region under normothermia, but not under hypothermic treatments. Furthermore, adenovirus-mediated overexpression of GRP78 protects rat hippocampal neurons from cell death and inhibits the rise in intracellular calcium concentration normally induced by hydrogen peroxide. These results suggest that reduction in GRP78 expression contributes to cell damage in the ischemic brain and that hypothermia-mediated restoration of GRP78 expression is one mechanism that enhances neuronal survival.
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PMID:Hypothermic treatment restores glucose regulated protein 78 (GRP78) expression in ischemic brain. 1168 83

It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH-DPAT-stimulated GTPgammaS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.
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PMID:Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors. 1221 56

A small reduction of body temperature during reperfusion following cerebral ischemia has been known to ameliorate neuronal injury. However, the mechanisms underlying postischemic hypothermia-induced neuroprotection are poorly understood. The burst of reactive oxygen species (ROS) formation that occurs during reperfusion has been documented to be involved in ischemic neuronal degeneration. In this study, we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 min in male Wistar rats. The body temperature was kept at 37 degrees C during ischemia and controlled at either 32 degrees C or 37 degrees C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2,3- and 2,5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine, while determining striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37 degrees C, the levels of 2,3- and 2,5-DHBA significantly increased after reperfusion. The peak levels of 2,3- and 2,5- DHBA were 2.9-fold and 2.7-fold increased above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.
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PMID:Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats. 1280 82

A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
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PMID:Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists. 1473 43

1. Hydrogen sulphide (H(2)S) acts as a gaseous cellular messenger and has recently been reported to induce a suspended animation-like state in mice. The aim of the present study was to investigate the protective role of H(2)S exposure in stress gastric ulcer. 2. In the present study, we used a rat model of water immersion and restraint stress (WRS) to induce the typical stress disease, namely stress gastric ulcer. Rats were treated with WRS for 4 h, with or without pre-exposure to H(2)S (160 p.p.m. H(2)S for 2.5 h). 3. In H(2)S-exposed rats, body temperature was significantly reduced by 2.5C (P < 0.01) and oxygen consumption was reduced by 37.1% (P < 0.01) compared with control rats. Plasma levels of H(2)S were increased by 20.8% (P < 0.01) following pre-exposure. Pre-exposure to H(2)S significantly reduced the gastric ulcer index, from 24 +/- 9 to 9 +/- 2 (P < 0.01), in WRS rats. In addition, WRS increased plasma levels of adrenocorticotropin (ACTH) and corticosterone 4.7- and 4.8-fold, respectively (both P < 0.01). Pre-exposure to H(2)S markedly suppressed plasma ACTH and corticosterone level by 34.4 and 53.2%, respectively (both P < 0.01), and reduced WRS-elevated myeloperoxidase (MPO) activity by 19%. In the present study, WRS increased gastric malondialdehyde and conjugated diene content by 42 and 68%, respectively (both P < 0.01), and H(2)S exposure reduced lipid peroxide production. Finally, H(2)S exposure inhibited the WRS-elevated expression of glucose-regulated protein 78 and caspase 12, markers of endoplasmic reticulum stress. 4. In conclusion, a low concentration of H(2)S may be a new pharmacological tool for induced hypothermia to prevent severe stress-induced diseases and multifarious trauma in the clinical setting.
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PMID:Hydrogen sulphide-induced hypothermia attenuates stress-related ulceration in rats. 1794 93

Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.
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PMID:Hydrogen sulphide and its therapeutic potential. 1794 22

Mild hypothermia and pharmacological postconditioning are widespread therapeutical treatment options that positively influence the clinical outcome after tissue hypoxia. In the study presented, a two-enzyme based in-vitro oxygen deficiency model in combination with cultured HT-1080 fibrosarcoma cells was employed to mimic the in-vivo situation of hypoxia and to evaluate the influence of mild hypothermia and postconditioning with catalase on hypoxia-mediated cell damage. Using the in-vitro oxygen deficiency model, partial pressure of oxygen was rapidly reduced to levels below 5mmHg in the culture media and cells responded with an increased expression of hypoxia inducible factor-1 on protein level. Hypoxia resulted in significant cell rounding and retraction of cytoplasmic cell extensions. Evaluation of cytotoxicity revealed a 3.5-fold increase in lactate dehydrogenase levels which was accompanied by 40-fold elevated levels of hydrogen peroxide. The hypoxia-induced increase of lactate dehydrogenase was 2.5-fold reduced in the hypothermia group, although morphological correlates of cytotoxicity were still visible. Hypothermia did not significantly influence hydrogen peroxide concentrations in the culture media. Pharmacological postconditioning with catalase however dose-dependently decreased hypoxia-induced lactate dehydrogenase release. This cytoprotective effect was accompanied by a dose-dependent, up to 50-fold reduction of hydrogen peroxide concentrations and retention of normal cell morphology. We suggest that the described in-vitro oxygen deficiency model is a convenient and simple culture system for the investigation of cellular and subcellular events associated with oxygen deficiency. Moreover, our in-vitro results imply that catalase postconditioning may be a promising approach to attenuate hypoxia-induced and hydrogen peroxide-mediated cell and tissue damage.
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PMID:Hypoxia-induced cell damage is reduced by mild hypothermia and postconditioning with catalase in-vitro: application of an enzyme based oxygen deficiency system. 1991 79

Induced hypothermia after cardiopulmonary resuscitation provides organ protection and is currently considered standard of care in clinical practice. An increasing number of reports indicate that induced hypothermia is also beneficial in other conditions of hypoxia-induced organ injury, including brain injury, intestinal ischaemia-reperfusion injury and acute lung injury. The mechanism of the protective effect is thought to be caused by a reduction in metabolism. A hibernation-like state, characterised by hypothermia, bradypnoea and a reduction in metabolic rate, was induced in animals that normally do not hibernate, after inhalation of hydrogen sulphide. This state was termed a 'suspended animation-like state'. In critically ill patients, an exaggerated systemic inflammatory response is common, which often results in multiple organ injury. Inducing a hypometabolic state during critical illness may limit organ injury by reducing oxygen consumption, constituting a fascinating new therapeutic perspective for the treatment of critically ill patients. In this manuscript, we describe mitochondrial dysfunction during critical illness and preclinical data that suggest a potential therapeutic possibility of lowering metabolism. In addition, we discuss issues that warrant further research before clinical applicability.
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PMID:Induction of a hypometabolic state during critical illness - a new concept in the ICU? 2050 67


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