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

Hypothermia has been demonstrated to be an effective neuroprotective strategy in a number of models of ischaemic and excitotoxic neurodegeneration in vitro and in vivo. Reduced glutamate release and free radical production have been postulated as potential mechanisms underlying this effect but no definitive mechanism has yet been reported. In the current study, we have used oxygen-glucose deprivation in organotypic hippocampal slice cultures as an in vitro model of cerebral ischaemia. When assessed by propidium iodide fluorescence, reducing the temperature during oxygen-glucose deprivation to 31-33 degrees C was significantly neuroprotective but this effect was lost if the initiation of hypothermia was delayed until the post-insult recovery period. The neuroprotective effects of hypothermia were associated with a significant decrease in both nitric oxide production, as assessed by 3-amino-4-aminomethyl-2',7'-difluorofluorescein fluorescence, and superoxide formation. Further, hypothermia significantly attenuated NMDA-induced nitric oxide formation in the absence of hypoxia/hypoglycaemia. We conclude that the neuroprotective effects of hypothermia are mediated through a reduction in nitric oxide and superoxide formation and that this effect is likely to be downstream of NMDA receptor activation.
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PMID:Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices. 1544 66

Lactate is considered an alternative substrate that is capable of replacing glucose in maintaining synaptic function in adult neurons. But, we found recently that lactate could be utilized for maintenance of synaptic potentials only after the activation of NMDA and voltage-dependent-calcium channel during glucose deprivation. To clarify more on the relationship between glycolysis and induction of lactate utilization, we tested lower concentration of glucose with hypoxia to induce a relative shortage of anaerobic energy production. Population spikes are not maintained with lactate following hypoxia in 10 mM glucose medium, but are maintained at their original levels with lactate after exposure to hypoxia in lower concentration (5 mM) of glucose. Hypothermia during low glucose-hypoxia, bath application of the NMDA channel blocker and the voltage-sensitive calcium channel blocker, as well as the omission of extracellular calcium prevented the induction of the lactate-supported population spikes. ATP levels in the tissue slices are relatively preserved in the conditions that block the induction of lactate-supported population spikes. From these observations, we propose that the energy source for maintenance of synaptic function in adult neuron changes from adult form (glucose alone) to immature one (glucose and/or lactate) after short of glucose supply.
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PMID:Glycolysis regulates the induction of lactate utilization for synaptic potentials after hypoxia in the granule cell of guinea pig hippocampus. 1556 84

Ischemia of intact dorsal root ganglia (DRG) in situ leads to massive neuron death due to ischemia-triggered secondary events, such as massive release of excitatory amino acids from the neurons, their excessive accumulation and activation of neuron NMDA and other receptors, acidification, and loss of calcium homeostasis. The present experiments tested whether hypothermia and alkalinization, separately or combined, provide neuroprotection against 1-4 hours of ischemia to the neurons within intact DRG acutely removed from organ donors. DRG under hypothermic (20-15 degrees C) or alkaline (pH 8.0-9.3) conditions yielded more viable neurons than DRG maintained under physiological conditions (37 degrees C/pH 7.4), 4.1-fold vs. 7.8-fold respectively, but, hypothermia and alkalinization combined (20 degrees C/pH 9.3) increased the yield of viable neurons 26-fold compared to DRG maintained under physiological conditions. These results show that combined hypothermia and alkalinization provide adult human DRG neurons significant neuroprotection against ischemia, and ischemia-induced causes of neuron death.
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PMID:Neuroprotection of adult human neurons against ischemia by hypothermia and alkalinization. 1688 78

The use of general anaesthetics has facilitated great advantages in surgery within the last 150 years. General anaesthesia is composed of several components including analgesia, amnesia, hypnosis and immobility. To achieve these components, general anaesthetics have to act via multiple molecular targets at different anatomical sites in the central nervous system. Much of our current understanding of how anaesthetics work has been obtained within the last few years on the basis of genetic approaches, in particular knock-out or knock-in mice. Anaesthetic drugs can be grouped into volatile and intravenous anaesthetics according to their route of administration. Common volatile anaesthetics induce immobility via molecular targets in the spinal cord, including glycine receptors, GABA(A) receptors, glutamate receptors, and TREK-1 potassium channels. In contrast, intravenous anaesthetics cause immobility almost exclusively via GABA(A) receptors harbouring beta3 subunits. Hypnosis is predominantly mediated by beta3-subunit containing GABA(A) receptors in the brain, whereas beta2 subunit containing receptors, which make up more than 50% of all GABA(A) receptors in the central nervous system, mediate sedation. At clinically relevant concentrations, ketamine and nitrous oxide block NMDA receptors. Unlike all other anaesthetics in clinical use they produce analgesia. Not only desired actions of anaesthetics, but also undesired side effects are linked to certain receptors. Respiratory depression involves beta3 containing GABA(A) receptors whereas hypothermia is largely mediated by GABA(A) receptors containing beta2 subunits. These recent insights into the clinically desired and undesired actions of anaesthetic agents provide new avenues for the design of drugs with an improved side-effect profile. Such agents would be especially beneficial for the treatment of newborn children, elderly patients and patients undergoing ambulatory surgery.
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PMID:Anaesthetic drugs: linking molecular actions to clinical effects. 1707 66

It is generally assumed that neuronal cell death is minimal in liver failure and is insufficient to account for the neuropsychiatric symptoms characteristic of hepatic encephalopathy. However, contrary to this assumption, neuronal cell damage and death are well documented in liver failure patients, taking the form of several distinct clinical entities namely acquired (non-Wilsonian) hepatocerebral degeneration, cirrhosis-related Parkinsonism, post-shunt myelopathy and cerebellar degeneration. In addition, there is evidence to suggest that liver failure contributes to the severity of neuronal loss in Wernicke's encephalopathy. The long-standing nature of the thalamic and cerebellar lesions, over 80% of which are missed by routine clinical evaluation, together with the probability that they are nutritional in origin, underscores the need for careful nutritional management (adequate dietary protein, Vitamin B(1)) in liver failure patients. Mechanisms identified with the potential to cause neuronal cell death in liver failure include NMDA receptor-mediated excitotoxicity, lactic acidosis, oxidative/nitrosative stress and the presence of pro-inflammatory cytokines. The extent of neuronal damage in liver failure may be attenuated by compensatory mechanisms that include down-regulation of NMDA receptors, hypothermia and the presence of neuroprotective steroids such as allopregnanolone. These findings suggest that some of the purported "sequelae" of liver transplantation (gait ataxia, memory loss, confusion) could reflect preexisting neuropathology.
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PMID:Neuronal cell death in hepatic encephalopathy. 1785 42

The noble gas xenon exerts favorable anesthetic properties along with remarkable hemodynamic stability in healthy patients undergoing elective surgery. Recent investigations documented that it does not prolong the duration of widely used neuromuscular blocking agents, including mivacurium and rocuronium. Some studies also suggest reduced neurocognitive compromise in the very early phase after general anesthesia. These properties differ from those observed for conventional inhalational anesthetics like isoflurane, desflurane and sevoflurane. However, a wider use of xenon in daily clinical routine has been limited owing to its higher price and technical restraints regarding economic delivery. Although there are controversial opinions, xenon seems to exert its main anesthetic features via the glutamate receptor. Recently, a novel binding cavity on the NMDA-subtype glutamate receptor has been elucidated that is occupied by xenon as well as isoflurane. Studies utilizing advanced imaging technologies have furthermore revealed that xenon markedly suppresses cerebral blood flow and glucose metabolism in distinct regions of the human brain. These investigations promise to further the understanding of the basic mechanisms underlying the induction and maintenance of anesthesia in general. Results from in vitro studies and various animal models have consistently demonstrated organoprotective properties of xenon, mainly in settings of ischemia and reperfusion injury. Interestingly, these effects have frequently been observed at subanesthetic concentrations and seem to be synergistic when used in combination with therapeutic hypothermia. Future studies will have to prove whether the high costs of xenon administration might be outweighed by its ability to substantially reduce the sequelae of myocardial and cerebral ischemia.
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PMID:Xenon: recent developments and future perspectives. 1847 53

Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-l-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dose-dependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (delta Tcor) was determined. There was hypothermia in the mild toxidrome (delta Tcor<-1 degrees C), high hyperthermia in the severe toxidrome (delta Tcor>+2 degrees C) and a small change in T(cor) in the moderate toxidrome (-1 degrees C<delta Tcor<+2 degrees C). Thus, delta Tcor in response to drugs can be used to estimate the severity of the toxidrome. The second attempt was to identify the receptors mediating those changes. 5-HT1A receptors were involved in the hypothermic response while 5-HT2A and NMDA receptors mediated head shakes, hyperthermia, forepaw treading and Straub tail. Lastly, antidotal effect of cyproheptadine and (+)-MK-801 was examined. Both drugs blocked hyperthermia and death. However, the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced. These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5-HT toxidrome.
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PMID:Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats. 1849 1

The aim of the present investigation was to analyze the molecular mechanism(s) of diazepam neuroprotection in two models of selective neuronal death in CA1 sector of hippocampus: in vivo following transient gerbil brain ischemia and in vitro in rat hippocampal brain slices subjected to glutamatergic (100 microM NMDA) or oxidative (30 microM tertbutyl-hydroksyperoxide (TBH)) stress. In the in vivo model the diazepam treatment (two doses of 10mg/kg i.p. 30 and 90 min after the insult) resulted in more than 60% of CA1 hippocampal neurons surviving the insult comparing with 15% in untreated animals. To test whether the protective effect of diazepam was due to the postulated drug-induced hypothermia we followed the fluxes of body temperature during postischemic reperfusion: diazepam reduced temperature from 36.6+/-1 degrees C to 33.4+/-2 degrees C. Equivalent hypothermia induced and maintained in animals after ischemia did not prevent neuronal cell loss to the same extent as diazepam did (42.8+/-9.2% and 72.4+/-14.5% of live neurons, respectively). In vitro, under constant temperature conditions, diazepam exerted neuroprotective effects following a "U-shaped" dose-response curve, with concentration efficacy window of 0.5-10 microM. Five micro-molar diazepam showed significant protection by reducing over 50% the number of (dead) propidium iodide labeled cells even in the presence of GABA(A) receptor antagonist bicuculline. Next, we have shown that diazepam reduced the efflux of cytochrome c out of mitochondria both in compromised CA1 neurons in vitro and in isolated mitochondria treated with 30 microM THB. Our results suggest that the neuroprotective action of diazepam relies on additional mechanism(s) and not solely on its hypothermic effect. We suggest that diazepam evokes neuroprotection through its central receptors located on the GABA(A) receptor complex and, possibly, through its peripheral receptor, the translocator protein TSPO (previously called the peripheral benzodiazepine receptor) located in the outer mitochondrial membrane.
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PMID:Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABAAR and hypothermic effects. 1942 22

Inhibition of the initial events occurring immediately after ischemia-reperfusion seems to be beneficial for reducing the extent of subsequent chronic neuronal cell injury. We investigated the effects of moderate hypothermia (32 degrees C) commencing 30 min before ischemia on reactive hyperemia by measuring cerebral blood flow (CBF) with a laser-Doppler flowmeter at the initial ischemia-reperfusion stage (60 min) following 10 min of global cerebral ischemia in rats. In normothermia, CBF was increased to approximately 240% and decreased thereafter, although it remained at approximately 150% after 60 min of ischemia-reperfusion. In contrast, hypothermia increased CBF to more than 270% after ischemia-reperfusion, then recovered to the basal level within 30 min. The period of reactive hyperemia under normothermia tended to be shortened by pre-administration of an NMDA antagonist, in a manner similar to hypothermia. Furthermore, hypothermia inhibited the presence of cells with caspase-3-like immunoreactivity in the hippocampal CA1 sector after 8 h of ischemia-reperfusion. Our findings indicate that hypothermia tends to shorten the period of reactive hyperemia during the initial ischemia-reperfusion stage. This phenomenon may be partly associated with activation of NMDA receptors and a beneficial effect of hypothermia in resisting progression of the neurotoxic cascade in the first 8 h after ischemia-reperfusion.
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PMID:Measurement of cerebral reactive hyperemia at the initial post-ischemia reperfusion stage under normothermia and moderate hypothermia in rats. 2003 16

Hepatocerebral disorders are serious neuropsychiatric conditions that result from liver failure. These disorders are characterized neuropathologically by varying degrees of neuronal cell death in basal ganglia, cerebellum, and spinal cord, and include clinical entities such as Wilson's Disease, post-shunt myelopathy, hepatic encephalopathy, and acquired non-Wilsonian hepatocerebral degeneration. Morphologic changes to astrocytes (Alzheimer type II astrocytosis) are a major feature of hepatocerebral disorders. Neurological symptoms include Parkinsonism, cognitive dysfunction, and ataxia. Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders include ammonia toxicity and neurotoxic effects of metals such as copper, manganese, and iron. Molecular mechanisms of neurotoxicity include oxidative/nitrosative stress, glutamate (NMDA)-receptor-mediated excitotoxicity, and neuroinflammatory mechanisms. However, neuronal cell death in hepatocerebral disorders is limited by adaptive mechanisms that may include NMDA-receptor down-regulation, the synthesis of neuroprotective steroids and hypothermia. Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease), the use of ammonia-lowering agents (lactulose, antibiotics, ornithine aspartate) and liver transplantation.
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PMID:Metal toxicity, liver disease and neurodegeneration. 2036 13


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