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

This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36-37 degrees C or allowed to fall passively to 28-32 degrees C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2-CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.
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PMID:Regionally selective effects of NMDA receptor antagonists against ischemic brain damage in the gerbil. 182 9

Degeneration of hippocampal CA1 neurons occurs following transient complete ischemia produced by raised intracranial pressure. Both systemic injection of MK-801 and profound cerebral hypothermia produced by cisternal infusion of room temperature (22-25 degrees C) fluids protect vulnerable CA1 neurons from degeneration. Hypothermia appears to decrease hippocampal extracellular levels of glutamate during and after ischemia but provides only relative protection from ischemia as CA1 degeneration does occur with prolonged (30 min) periods of ischemia. Elevated intracranial pressure appears to produce ischemic degeneration in the hippocampus via an NMDA receptor mediated excitotoxic process which is highly temperature dependent.
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PMID:Degeneration of hippocampal CA1 neurons following transient ischemia due to raised intracranial pressure: evidence for a temperature-dependent excitotoxic process. 197 Sep 44

Prolonged (2-6 h) cooling of monolayer cultures of dissociated murine spinal cord at temperatures below 17 degrees C caused pronounced swelling of neuronal perikarya and dendrites. The numbers of swollen neurons in a culture increased as the temperature was reduced, and at 7 degrees C-10 degrees C all of the neurons were swollen. On rewarming the cultures to 37 degrees C, the majority of the swollen neurons died (up to 74% at 10 degrees C). Glial cells were not affected. Addition of the NMDA antagonists D-2-amino-5-phosphonovalerate (DAPV, 100 microM), ketamine (100 microM), and dibenzocyclohepteneimine (MK801, 10 microM) to spinal cord cultures before lowering the temperature to 10 degrees C minimized the dendrosomatic swelling and reduced neuronal mortality from 74% to 10%. These data show a surprising sensitivity of some neurons to nonfreezing low temperatures and suggest direct involvement of the NMDA receptor in hypothermia-related neuronal death.
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PMID:NMDA antagonists prevent hypothermic injury and death of mammalian spinal neurons. 198 14

An accumulation of experimental data suggests that N-methyl-D-aspartate (NMDA) receptor antagonists will prevent ischemic neuronal injury following transient global ischemia and reduce infarct volumes following focal ischemic insults. The excitotoxic hypothesis states that the excitatory amino acid neurotransmitter L-glutamate has neurotoxic properties that can be attenuated by antagonism of the NMDA receptor. In vitro work has shown that a variety of NMDA antagonists will prevent the death of neurons grown in culture and subsequently exposed to either brief periods of hypoxia or glutamate exposure. In vivo it has been shown that glutamate is released following ischemia, that the NMDA receptors remain functional both during and following ischemia, and that the concentration of NMDA receptors is highest in those regions that are most sensitive to ischemic neuronal injury. Once stimulated, these receptors mediate a lethal influx of calcium. Experiments with global ischemia have reported a cytoprotective effect by either prior removal of glutamate afferents or pretreatment with either competitive or noncompetitive receptor antagonists. Some of these data have been challenged and one suggestion that has been made is that the observed pharmacoprotection may be the result of coincidental drug-induced hypothermia. Numerous studies using a variety of models of focal ischemia have shown that the volume of a cortical infarct can be reduced with NMDA antagonists given either before or after an ischemic insult. These data are more consistent than those achieved for models of global ischemia and have led to proposals for clinical trials. Novel compounds that antagonize the NMDA receptor are now the subject of phase I clinical studies that are envisaged as a prelude to randomized acute stroke trials. The hypothesis that blockade of excitatory amino acid receptors will prevent neuronal death presages a new era in acute stroke treatment.
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PMID:Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? 214 95

Several laboratories have reported a significant reduction of ischemia-induced injury to hippocampal neurons in rodents treated with competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonists. This study examined the effects of the noncompetitive antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in Mongolian gerbils subjected to 5 min of bilateral carotid artery occlusion. In adult female gerbils, single doses of MK-801 injected 1 hr prior to ischemia significantly (p less than 0.01) reduced damage to CA1 hippocampal neurons. However, the drug rendered the postischemic animals comatose and hypothermic for several hours compared with the saline-treated animals. In subsequent experiments, animals pretreated with MK-801 and maintained normothermic during and after forebrain ischemia demonstrated no amelioration of hippocampal damage. Gerbils not treated with MK-801, but kept hypothermic in the postischemic period to approximately the same degree (34.5 degrees C) and duration (8 hr) as was induced by MK-801 therapy showed significant (p less than 0.01) protection of CA1 neurons against ischemia. The neuroprotective activity of MK-801 against transient global ischemia appears to be largely a consequence of postischemic hypothermia rather than a direct action on NMDA receptor-channels.
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PMID:Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. 1581 67

In vitro ischemia models have utilized oxygen, or oxygen and glucose deprivation to simulate ischemic neuronal injury. Combined oxygen and glucose deprivation can induce neuronal damage which is in part mediated through NMDA receptors. Severe oxygen deprivation alone however can cause neuronal injury which is not NMDA mediated. We tested the hypothesis that NMDA, or non-NMDA receptor mediated mechanisms may predominate, to induce neuronal injury following severe oxygen deprivation depending on the presence of glucose. We found that NMDA receptor blockade using dizocilpine (MK-801), DL-2-amino-5-phosphonovaleric acid (APV), or CGS 19755, was highly effective in reducing CA1 injury in organotypic hippocampal cultures, caused by complete oxygen and glucose deprivation. Complete oxygen deprivation alone however, caused CA1 neuronal injury which was not diminished using NMDA receptor blockade alone with MK-801 or APV, or in combination with AMPA/kainate receptor blockade using 6-cyano-7-dinitroquinoxalone-2,3-dione (CNQX). Neuronal protective strategies which act primarily through non-glutamate dependent mechanisms, including hypothermia, low chloride and calcium, and the free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN), provided neuronal protection against complete oxygen, as well as combined oxygen/glucose deprivation. Raising the pH using Hepes buffer during complete oxygen deprivation did not result in neuronal protection by NMDA receptor blockade. Partial oxygen deprivation alone, partial oxygen deprivation combined with glucose deprivation, glucose deprivation alone, and also glutamate exposure, all produced neuronal damage that was reduced by NMDA receptor blockade. The presence of glucose during complete oxygen deprivation appears to prevent glutamate receptor blockade from reducing neuronal injury in organotypic hippocampal cultures.
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PMID:Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures. 747 21

The effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 micrograms/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, L-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of L-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative effects of NG-monomethyl-L-arginine and MK-801 on the abstinence syndrome in morphine-dependent mice. 751 22

We examined the effect of moderate hypothermia (30 degrees C) on neuronal injury in murine cortical cell cultures. Lowering the temperature during and after a period of oxygen-glucose deprivation reduced both the release of glutamate to the bathing medium and accompanying neuronal degeneration. Hypothermia immediately after brief exposure to high concentrations of NMDA or glutamate also reduced the resulting neuronal degeneration. This protective effect was not eliminated when MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione were added immediately after washout of the exogenously added excitotoxin, suggesting that it was mediated by actions additional to reduction of endogenous late glutamate release. Hypothermia applied only during exposure to NMDA or glutamate, whether brief or prolonged, did not reduce subsequent cytosolic calcium accumulation or neuronal degeneration, suggesting that the postsynaptic induction of NMDA receptor-mediated excitotoxicity is not sensitive to temperature reduction. However, hypothermia during prolonged S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate exposure did reduce neuronal degeneration.
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PMID:Neuroprotective effect of hypothermia in cortical cultures exposed to oxygen-glucose deprivation or excitatory amino acids. 752 91

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are involved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor-mediated excitotoxic neuronal death. If this mechanism of "secondary" or "weak" excitotoxicity plays a role in neurodegenerative disease, NMDA antagonists and other "antiexcitotoxic" strategies may have therapeutic potential for these diseases.
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PMID:Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate. 752 65

Mongolian gerbils were subjected to transient forebrain ischaemia by occluding both common carotid arteries for 7 min. Subcutaneous administration of either the kappa-opioid receptor agonist enadoline (CI-977; 1 mg kg-1), or the non-competitive NMDA receptor antagonist dizocilpine (MK-801; 3 mg kg-1), at induction of ischaemia prevented neurodegeneration of CA1-CA2 pyramidal neurones in the dorsal hippocampus. It was shown by continuously monitoring intrahippocampal temperature that brain temperature drops by approximately 4 degrees C during ischaemia, when rectal temperature is maintained normothermic. Enadoline at no time point tested affected brain temperature, whereas dizocilpine statistically lowered brain temperature following ischaemia. These findings suggest that enadoline affords neuroprotection in the absence of any hypothermic episode, whilst in the case of dizocilpine, the small transient hypothermia observed following ischaemia may act synergistically or additively with the drug to yield neuroprotection.
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PMID:Brain temperature and the neuroprotective action of enadoline and dizocilpine in the gerbil model of global ischaemia. 831 52


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