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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A double blind controlled trial of ornithine alpha-ketoglutarate (OAKG) was carried out on 50 patients admitted to the Royal Free and Royal Northern Hospitals, London, suffering from a recent stroke. Significant improvement was found in patients treated with OAKG when examined on the fifth day of therapy as compared to their control cases. The therapy was given for 5 days. When the patients in the treated and the control groups were compared 10 days after the beginning of treatment, there were no differences between the 2 groups. Implications of these findings are discussed.
Stroke
PMID:Controlled trial of ornithine alpha ketoglutarate (OAKG) in patients with stroke. 34 38

Hypoxia is well known to cause an increase in brain anaerobic glycolysis. Ornithine alpha ketoglutarate (OAKG) given to six dogs was shown to attenuate these metabolic disturbances caused by hypoxia. Brain oxygen utilization was higher after ornithine alpha ketoglutarate during hypoxia than during a period of hypoxia alone. It is suggested that the clinical usefulness of OAKG should be explored in those situations where there is cerebral hypoxia or ischemia.
Stroke
PMID:Effect of ornithine alpha ketoglutarate (OAKG) on the response of brain metabolism to hypoxia in the dog. 64 19

Heat stroke was induced in intact rats in a thermal chamber (45 degrees C) and simultaneously a group of animals was subjected to overheating for the same time but was given intraperitoneal injections of ionol (120 mg/kg) for 2 days and 30 minutes before exposure in the chamber. Significant increase of the concentration of intermediates--lactate, pyruvate, malate, glutamate, ammonia--and decrease of the alpha-ketoglutarate content occurred in the renal tissue in animals of both groups. The NAD/NADH ratio in the cytoplasm and mitochondria reduced essentially, to a greater degree in animals given ionol injections. The last named were distinguished by higher survival and lower degree of hyperthermia.
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PMID:[The effect of ionol on oxidative-reductive processes in the kidney during heat stroke]. 261 12

The present study was undertaken to determine whether naftidrofuryl oxalate, a cerebral vasodilator, may improve or attenuate microsphere embolism-induced damage to the mitochondrial tricarboxylic acid cycle. For this purpose, the intermediates in the tricarboxylic acid cycle were determined using cerebral cortex isolated from microsphere-injected rats with and without naftidrofuryl oxalate treatment. Seven-hundred microspheres, with a diameter of 48 microns were injected into the right hemisphere through the right common carotid artery. The presence of cerebral infarction on the 3rd day after the operation was confirmed by the development of triphenyltetrazolium chloride-unstained areas in brain sections. Succinate, fumarate, malate, citrate and alpha-ketoglutarate, but not oxaloacetate, contents were significantly decreased in the right hemisphere of rats on the 3rd day following microsphere embolism. In the left hemisphere, a similar but smaller decrease in these intermediates was seen. The rats, which showed typical stroke-like symptoms, were treated with 15 mg/kg naftidrofuryl oxalate i.p., twice daily for 2.5 days, resulting in a significant reversal of the intermediate content of both hemispheres toward the control and an increased in the triphenyltetrazolium-stained area of a coronal section of the right hemisphere relative to the untreated animals. The results suggest that naftidrofuryl oxalate attenuates the development of microsphere embolism-induced cerebral infarction and improves microsphere-induced impairment of the mitochondrial tricarboxylic acid cycle. The observed effects provided evidence for a possible site of action of the agent on ischemic brain energy metabolism.
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PMID:Effects of naftidrofuryl oxalate on microsphere embolism-induced changes in tricarboxylic acid cycle intermediates of rats. 768 6

Experiments were conducted on male albino rats to study some intracellular metabolites (lactate, pyruvate, malate, glutamate, alpha-ketoglutarate, ammonia) and the redox process in the tissues of the liver, kidneys, myocardium, and skeletal muscles during hyperthermia (40 degrees C for one hour and 45 degrees C for one hour). Changes of the metabolite content and shifts in the redox process in the direction of oxidation in the liver and kidneys at both levels of hyperthermia are evidence of the development of tissue hypoxia of circulatory character in these organs. The mitochondrial NAD/NADH ratio in the myocardium reduced in moderate hyperthermia and increased during a heat stroke. There were no signs of cellular hypoxia in the skeletal muscles. It is concluded on basis of the results that changes of the blood flow in the organs play the leading role in the origin of thermal hypoxia.
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PMID:[Intracellular oxidative-reductive processes in tissues in hyperthermia]. 805 76

Structural and functional integrity of brain function profoundly depends on a regular oxygen and glucose supply. Any disturbance of this supply becomes life threatening and may result in severe loss of brain function. In particular, reductions in oxygen availability (hypoxia) caused by systemic or local blood circulation irregularities cannot be tolerated for longer periods due to an insufficient energy supply to the brain by anaerobic glycolysis. Hypoxia has been implicated in central nervous system pathology in a number of disorders including stroke, head trauma, neoplasia and neurodegenerative disease. Complex cellular oxygen sensing systems have evolved for tight regulation of oxygen homeostasis in the brain. In response to variations in oxygen partial pressure (P(O(2))) these induce adaptive mechanisms to avoid or at least minimize brain damage. A significant advance in our understanding of the hypoxia response stems from the discovery of the hypoxia inducible factors (HIF), which act as key regulators of hypoxia-induced gene expression. Depending on the duration and severity of the oxygen deprivation, cellular oxygen-sensor responses activate a variety of short- and long-term energy saving and cellular protection mechanisms. Hypoxic adaptation encompasses an immediate depolarization block by changing potassium, sodium and chloride ion fluxes across the cellular membrane, a general inhibition of protein synthesis, and HIF-mediated upregulation of gene expression of enzymes or growth factors inducing angiogenesis, anaerobic glycolysis, cell survival or neural stem cell growth. However, sustained and prolonged activation of the HIF pathway may lead to a transition from neuroprotective to cell death responses. This is reflected by the dual features of the HIF system that include both anti- and proapoptotic components. These various responses might be based on a range of oxygen-sensing signal cascades, including an isoform of the neutrophil NADPH oxidase, different electron carrier units of the mitochondrial chain such as a specialized mitochondrial, low P(O(2)) affinity cytochrome c oxidase (aa(3)) and a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF prolyl-hydroxylase (PHD) and HIF asparaginyl hydroxylase, known as factor-inhibiting HIF (FIH-1). Thus specific oxygen-sensing cascades, by means of their different oxygen sensitivities, cell-specific and subcellular localization, may help to tailor various adaptive responses according to differences in tissue oxygen availability.
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PMID:Cellular oxygen sensing need in CNS function: physiological and pathological implications. 1529 39

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1alpha and HIF-2alpha. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1alpha and up-regulate HIF-dependent target genes (e.g. enolase, p21(waf1/cip1), vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.
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PMID:Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. 1622 10

Studies of adaptive mechanisms to hypoxia led to the discovery of the transcription factor called hypoxia inducible factor (HIF). HIF is a ubiquitously expressed, heterodimeric transcription factor that regulates a cassette of genes that can provide compensation for hypoxia, metabolic compromise, and oxidative stress including erythropoietin, vascular endothelial growth factor, or glycolytic enzymes. Diseases associated with oxygen deprivation and consequent metabolic compromise such as stroke or Alzheimer's disease may result from inadequate engagement of adaptive signaling pathways that culminate in HIF activation. The discovery that HIF stability and activation are governed by a family of dioxygenases called HIF prolyl 4 hydroxylases (PHDs) identified a new target to augment the transcriptional activity of HIF and thus the adaptive machinery that governs neuroprotection. PHDs lose activity when cells are deprived of oxygen, iron or 2-oxoglutarate. Inhibition of PHD activity triggers the cellular homeostatic response to oxygen and glucose deprivation by stabilizing HIF and other proteins. Herein, we discuss the possible role of PHDs in regulation of both HIF-dependent and -independent cell survival pathways in the nervous system with particular attention to the co-substrate requirements for these enzymes. The emergence of neuroprotective therapies that modulate genes capable of combating metabolic compromise is an affirmation of elegant studies done by John Blass and colleagues over the past five decades implicating altered metabolism in neurodegeneration.
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PMID:Hypoxia inducible factor prolyl 4-hydroxylase enzymes: center stage in the battle against hypoxia, metabolic compromise and oxidative stress. 1734 11

Most homeostatic processes including gene transcription occur as a result of deviations in physiological tone that threatens the survival of the organism. A prototypical homeostatic stress response includes changes in gene expression following alterations in oxygen, iron or 2-oxoglutarate levels. Each of these cofactors plays an important role in cellular metabolism. Accordingly, a family of enzymes known as the Prolyl 4-hydroxylase (PHD) enzymes are a group of dioxygenases that have evolved to sense changes in 2-oxoglutarate, oxygen and iron via changes in enzyme activity. Indeed, PHDs are a part of an established oxygen sensor system that regulates transcriptional regulation of hypoxia/stress-regulated genes and thus are an important component of events leading to cellular rescue from oxygen, iron or 2-oxoglutarate deprivations. The ability of PHD activity to regulate homeostatic responses to oxygen, iron or 2-oxoglutarate metabolism has led to the development of small molecule inhibitors of the PHDs as a strategy for activating or augmenting cellular stress responses. These small molecules are proving effective in preclinical models of stroke and Parkinson's disease. However the precise protective pathways engaged by PHD inhibition are only beginning to be defined. In the current review, we summarize the role of iron, 2-oxoglutarate and oxygen in the PHD catalyzed hydroxylation reaction and provide a brief discussion of some of the transcription factors that play an effective role in neuroprotection against oxidative stress as a result of changes in PHD activity.
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PMID:Prolyl 4-hydroxylase activity-responsive transcription factors: from hydroxylation to gene expression and neuroprotection. 1798 60

A major challenge for neurological therapeutics is the development of small molecule drugs that can activate a panoply of downstream pathways without toxicity. Over the past decade our group has shown that a family of enzymes that regulate posttranscriptional and transcriptional adaptive responses to hypoxia are viable targets for neuronal protection and repair. The family is a group of iron, oxygen, and 2-oxoglutarate-dependent dioxygenases, known as the HIF prolyl 4-hydroxylases (HIF PHDs). We have previously shown that pluripotent protection offered by iron chelators is mediated, in part, via the ability of these agents to inhibit the HIF PHDs. Our group and others have implicated the transcriptional activator HIF-1 in some of the salutary effects of iron chelation-induced PHD inhibition. While some iron chelators are currently employed in humans for conditions such as hemochromatosis, the diverse utilization of iron in physiological processes in the brain makes the development of HIF activators that do not bind iron a high priority. Here we report the development of a high throughput screen to develop novel HIF activators and/or PHD inhibitors for therapeutic use in the central nervous system (CNS). We show that tilorone, a low-molecular weight, antiviral, immunomodulatory agent is the most effective activator of the HIF pathway in a neuronal line. We also show that tilorone enhances HIF protein levels and increases the expression of downstream target genes independent of iron chelation and HIF PHD inhibition in vitro. We further demonstrate that tilorone can activate an HIF-regulated reporter gene in the CNS. These studies confirm that tilorone can penetrate the blood-brain barrier to activate HIF in the CNS. As expected from these findings, we show that tilorone provides effective prophylaxis against permanent ischemic stroke and traumatic spinal cord injury in male rodents. Altogether these findings identify tilorone as a novel and potent modulator of HIF-mediated gene expression in neurons with neuroprotective properties.
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PMID:Small molecule activation of adaptive gene expression: tilorone or its analogs are novel potent activators of hypoxia inducible factor-1 that provide prophylaxis against stroke and spinal cord injury. 1907 58


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