Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective agonists of adenosine A1, GABAa, GABAb, and alpha 2-receptors (inhibitory neurotransmitter analogs) have a high neuroprotective effects (NPE) on two models of complete cerebral ischemia (CI). These NPEs are specific as they are inhibited by selective antagonists and, in addition, the selective alpha 1- and beta-receptor agonists have no NPE. The natural resistance to CI is also associated with A- and alpha 1-receptors. NPE does not result from improved cerebral blood flow. The receptor agonists protect the brain itself. They use a tolerance strategy and hypothermia is an important component, but not the only mechanism of NPE. Unlike most drugs, receptor neuroprotectors (RNP) guard not only a penumbra zone, but the core of ischemia as they are effective in complete global CI. Moreover, RNP-induced delay of irreversible lesions may increase a therapeutical window for using other drugs. RNPs are promising potential drugs in CI.
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PMID:[Receptor agonists as perspective neuroprotective agents]. 1105 99

Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.
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PMID:Current aspects of pathophysiology and cell dysfunction after severe head injury. 1156 94

Neuroprotectants are drugs designed to treat stroke by preserving ischemic neurons in the penumbra. Despite numerous studies over the past ten years, no such drug has yet shown clinical efficacy. This article reviews those trials completed since 1999, including assessments of drugs that modify receptors or ion flow, block leukocyte adhesion receptors or stabilize membranes. In addition, ongoing trials and early trials using novel mechanisms of action, such as hypothermia and antioxidants, are discussed.
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PMID:An update of neuroprotectants in clinical development for acute stroke. 1189 36

Following a transient ischemic insult there is a marked increase in free radical (FR) production within the first 10-15 min of reperfusion and again at the peak of the inflammatory process. Hypothermia decreases lipid peroxidation following global ischemia, raising the possibility that it may act by reducing FR production early on and by maintaining or increasing endogenous antioxidant systems. By means of FR fluorescence, Western blot, immunohistochemistry, and enzymatic assay, we studied the effects of mild hypothermia on superoxide (O(-*)(2)) anion production, superoxide dismutase SOD expression, and activity following focal cerebral ischemia in rats. Mild hypothermia significantly reduced O(-*)(2) generation in the ischemic penumbra and corresponding contralateral region, but did not alter the bilateral SOD expression. SOD enzymatic activity in the ischemic core was slightly reduced in hypothermia-treated animals compared with normothermic controls. Our results suggest that the neuroprotective effect of mild hypothermia may be due, in part, to a reduction in neuronal and endothelial O(-*)(2) production during early reperfusion.
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PMID:Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. 1246 May 44

Acute stroke is the third most common cause of death and also the most common cause of permanent disability in industrialized countries. Ischemic stroke is caused by occlusion of a cerebral artery leading to a critical reduction in brain perfusion in the respective brain area (penumbra). Most acute stroke treatment strategies are based on the penumbra concept: attaining rapid and persistent reperfusion is followed by the protection of critically ischemic and not yet infarcted (penumbral) tissue by, e.g., neuroprotection. Examination of the acute stroke patient includes a brief history, neurostatus and imaging (CT or MRI) for the exclusion of intracerebral hemorrhage. The diagnostic standard is CT; modern stroke MRI protocols provide an improved selection in later time windows. Intravenous thrombolysis with rt-PA within 3 h of symptom onset is the only approved therapy with a proven significant benefit for the patient. The effect is smaller but still significant if treatment occurs up to 4.5 h, and may still be present in MRI selected patients up to 9 h. More aggressive forms of therapy include interventional reperfusion techniques and therapy of malignant MCA infarction such as hemicraniectomy and hypothermia, which at present, however, are not routine and are only performed in specialized centers.
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PMID:[Acute cerebral circulation problems]. 1597 Oct 52

Previously we showed that treatment with mild hypothermia (34 degrees C for 2 h) after a focal cerebral infarct was neuroprotective by reducing apoptosis in the penumbra (cortex), but not in the core (striatum) of the infarct. In this study we examined whether administration of N-acetyl-aspartyl-glutamate (NAAG) in combination with mild hypothermia could improve striatal neuroprotection in the endothelin-1 rat model. NAAG (10 mg/kg i.p.) was injected under normothermic (37 degrees C) or mild hypothermic conditions, either 40 min before or 20 min after the insult. NAAG reduced caspase 3 immunoreactivity in the striatum, irrespective of the time of administration and brain temperature. This neuroprotective effect could be explained, at least partially, by decreased nitric oxide synthase activity in the striatum and was blocked by the group II metabotropic glutamate receptor antagonist, LY341495. Hypothermia applied together with NAAG reduced both cortical and striatal caspase 3 immunoreactivity, as well as the overall ischaemic damage in these areas. However, no pronounced improvement was seen in total damaged brain volume. Extracellular glutamate levels did not correlate with the observed protection, whatever treatment protocol was applied. We conclude that treatment with NAAG causes the same degree of neuroprotection as treatment with hypothermia. Combination of the two treatments, although reducing apoptosis, does not considerably improve ischaemic damage.
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PMID:Neuroprotective effect of N-acetyl-aspartyl-glutamate in combination with mild hypothermia in the endothelin-1 rat model of focal cerebral ischaemia. 1613 71

Previously, we showed that treatment with resuscitative, post-ischaemic mild hypothermia (34 degrees C for 2 h) reduced apoptosis in the penumbra (cortex), but not in the core (striatum) of an endothelin-1 (Et-1)-induced focal cerebral infarct in the anaesthetized rat. Therefore, the purpose of this study was to investigate by which pathways resuscitative mild hypothermia exerts its neuroprotective effect in this model. The amino acids glutamate, serine, glutamine, alanine, taurine, arginine and the NO-related compound citrulline were sampled from the striatum and cortex of the ischaemic hemisphere using in vivo microdialysis. The in vivo salicylate trapping method was applied for monitoring hydroxyl radical formation via 2,3 dihydroxybenzoic acid (2,3 DHBA) detection. Caspase-3, neuronal nitric oxide synthase (nNOS) immunoreactivity and the volume of ischaemic damage were determined 24 h after the insult. In both the striatum and the cortex, Et-1-induced increases in glutamate, taurine and alanine were refractory to mild hypothermia. However, mild hypothermia significantly attenuated the ischaemia-induced 2,3 DHBA levels and the nNOS immunoreactivity in the cortex, but not in the striatum. These observations were associated with a decreased caspase-3 immunoreactivity. These results suggest that mild hypothermia exerts its neuroprotective effect in the penumbra partially by reducing nNOS activity and thereby preventing oxidative stress. Furthermore, we confirm our previous findings that the neuroprotective effect of resuscitative hypothermia is not mediated by changes in ischaemia-induced amino acid release as they could not be associated with the ischaemia-induced damage in the Et-1 rat model.
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PMID:Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. 1619 Aug 88

Neuroprotection of patients with acute ischemic stroke should start at the scene and continue in the ambulance with the assessment and treatment of the airway, breathing, circulation, body temperature, and blood glucose. The key goal in eligible patients should be fast vessel recanalization with intravenous recombinant tissue-type plasminogen activator Results from a meta-analysis suggest that systemic thrombolysis is effective when given within 4.5 hours after stroke onset. The time window extends to 6 hours for patients undergoing intravascular thrombolysis. Acute stroke patients should be admitted to stroke care units. A crucial component of neuroprotection is the prevention of secondary brain damage, which can be caused by hypoxemia, hypotension, hyperthermia and hyperglycemia. This can be achieved by avoiding complications, e.g. aspiration, and intensive control of oxygenation, hydration and blood pressure, body temperature, blood glucose, and cardiac monitoring. Neuroprotective agents are designed to try to salvage brain tissue within the penumbra. Thus far, despite promising preclinical studies, clinical trials with neuroprotective drugs in acute ischemic stroke have been disappointing. However, we have been able to identify many of the factors that were responsible for these failures, and better-designed clinical trials with neuroprotective drugs should look more promising. Mild induced hypothermia is another form of neuroprotective treatment that is currently being investigated in acute stroke.
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PMID:Neuroprotection in acute ischemic stroke. 1625 52

A three-dimensional mathematical model was developed to examine the transient and steady-state temperature distribution in the human brain during selective brain cooling (SBC) by unilateral intracarotid freezing-cold saline infusion. To determine the combined effect of hemodilution and hypothermia from the cold saline infusion, data from studies investigating the effect of these two parameters on cerebral blood flow (CBF) were pooled, and an analytic expression describing the combined effect of the two factors was derived. The Pennes bioheat equation used the thermal properties of the different cranial layers and the effect of cold saline infusion on CBF to propagate the evolution of brain temperature. A healthy brain and a brain with stroke (ischemic core and penumbra) were modeled. CBF and metabolic rate data were reduced to simulate the core and penumbra. Simulations using different saline flow rates were performed. The results suggested that a flow rate of 30 ml/min is sufficient to induce moderate hypothermia within 10 min in the ipsilateral hemisphere. The brain with stroke cooled to lower temperatures than the healthy brain, mainly because the stroke limited the total intracarotid blood flow. Gray matter cooled twice as fast as white matter. The continuously falling hematocrit was the main time-limiting factor, restricting the SBC to a maximum of 3 h. The study demonstrated that SBC by intracarotid saline infusion is feasible in humans and may be the fastest method of hypothermia induction.
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PMID:A theoretical model of selective cooling using intracarotid cold saline infusion in the human brain. 1725 67

Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (deltaPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on deltaPKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of deltaPKC (CF-deltaPKC) increased after stroke. Both hypothermia (30 degrees C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated deltaPKC in the penumbra. Other hallmarks of deltaPKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-deltaPKC increases in the mitochondria and nuclei. Conversely, a specific deltaPKC activator, psideltaRACK, decreased the neuroprotective effect of hypothermia. Finally, deltaPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of deltaPKC translocation. Both cytochrome c release and deltaPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing deltaPKC activation after stroke.
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PMID:Suppression of deltaPKC activation after focal cerebral ischemia contributes to the protective effect of hypothermia. 1729 47


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