Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide and other reactive nitrogen species appear to play several crucial roles in the brain. These include physiological processes such as neuromodulation, neurotransmission and synaptic plasticity, and pathological processes such as neurodegeneration and neuroinflammation. There is increasing evidence that glial cells in the central nervous system can produce nitric oxide in vivo in response to stimulation by cytokines and that this production is mediated by the inducible isoform of nitric oxide synthase. Although the etiology and pathogenesis of the major neurodegenerative and neuroinflammatory disorders (Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis) are unknown, numerous recent studies strongly suggest that reactive nitrogen species play an important role. Furthermore, these species are probably involved in brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. Recent evidence also indicates the importance of cytoprotective proteins such as heat shock proteins (HSPs) which appear to be critically involved in protection from nitrosative and oxidative stress. In this review, evidence for the involvement of nitrosative stress in the pathogenesis of the major neurodegenerative/ neuroinflammatory diseases and the mechanisms operating in brain as a response to imbalance in the oxidant/antioxidant status are discussed.
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PMID:NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. 1105 4

Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program. Widely shared features of metabolism in starvation, hibernation and various conditions of energy deprivation, e.g. ischemia, allow the definition of a deprivation syndrome which is a phylogenetically conserved adaptive response to energetic stress. It is characterized by hypometabolism, oxidative stress and adjustments of the glucose-fatty acid cycle. Cumulative evidence suggests that the brain in aging and AD actively adapts to the progressive fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble Abeta which inhibits glucose utilization and stimulates ketone body utilization at various levels. These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the key transmitter and effector systems regulating glucose metabolism. Hormonal and effector systems which promote ketone body utilization, such as glucocorticosteroid and galanin activity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketone body metabolizing enzymes, are enhanced. A multitude of risk factors feed into this pathophysiological cascade at a variety of levels. Taking into account its pleiotropic regulatory actions in the deprivation response, a new name for Abeta is suggested: deprivin. On the other hand, cumulative evidence, taken together compelling, suggests that senile plaques are the dump rather than the driving force of AD. Moreover, the neurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contribute significantly to the in vivo pathophysiological events. This archaic program, conserved from bacteria to man, aims to ensure the survival of a deprived organism and controls such divergent processes as sporulation, hibernation, aging and aging-related diseases. In contrast to the immature brain, ketone body utilization of the aged brain is no longer sufficient to meet the energetic demands and is later supplemented by lactate, thus recapitulating in reverse order the sequential fuel utilization of the immature brain. The transduction pathways which operate to switch metabolism also convey the programming and balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the reiteration of developmental processes such as transcription factor activation, tau hyperphosphorylation, and establishment of growth factor independence by means of Ca2+ set point shift. Thus, the increasing energetic insufficiency results in the progressive centralization of metabolic activity to the neuronal soma, leading to pruning of the axonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticity and, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration of vulnerable neurons. Finally, it is outlined that genetic (e.g. Down's syndrome, APP and presenilin mutations and apoE4) and environmental risk factors represent progeroid factors which accelerate the aging process and precipitate the manifestation of AD as a progeroid systemic disease. Aging and AD are related to each other by threshold phenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion, of a metabolic stress response.
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PMID:A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events. 1106 71

Nitric oxide and other reactive nitrogen species appear to play crucial roles in the brain such as neuromodulation, neurotransmission and synaptic plasticity, but are also involved in pathological processes such as neurodegeneration and neuroinflammation. Acute and chronic inflammation result in increased nitrogen monoxide formation and nitrosative stress. It is now well documented that NO and its toxic metabolite, peroxynitrite, can inhibit components of the mitochondrial respiratory chain leading to cellular energy deficiency and, eventually, to cell death. Within the brain, the susceptibility of different brain cell types to NO and peroxynitrite exposure may be dependent on factors such as the intracellular reduced glutathione and cellular stress resistance signal pathways. Thus neurons, in contrast to astrocytes, appear particularly vulnerable to the effect of nitrosative stress. Evidence is now available to support this scenario for neurological disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis and Huntington's disease, but also in the brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. To survive different types of injuries, brain cells have evolved integrated responses, the so-called longevity assurance processes, composed of several genes termed vitagenes and including, among others, members of the HSP system, such as HSP70 and HSP32, to detect and control diverse forms of stress. In particular, HSP32, also known as heme oxygenase-1 (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Increasing evidence suggests that the HO-1 gene is redox-regulated and its expression appears closely related to conditions of oxidative and nitrosative stress. An amount of experimental evidence indicates that increased rate of free radical generation and decreased efficiency of the reparative/degradative mechanisms, such as proteolysis, are factors that primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing such a response. These findings have led to new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel, cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes may possibly delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.
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PMID:Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. 1534 Nov 81

We report acute thromboembolic events in a 14-year-old boy with Down syndrome and repaired atrioventricular septal defect. He presented with sudden onset of bilateral lower limb ischemia. Transesophageal echocardiography detected a thrombus in the right atrium. An arterial saddle embolus was removed following bilateral iliac embolectomy. Despite anticoagulation, he presented again with sudden bilateral lower limb ischemia and respiratory distress. Multiple pulmonary emboli and a thrombus in the right atrium were noted on imaging studies. An arterial embolus was removed from the abdominal aorta at the bifurcation. To our knowledge, this is the first report of a child or adolescent with a repaired congenital heart lesion and arterial embolism requiring embolectomy. This association and possible etiological factors are discussed.
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PMID:Saddle arterial embolus in a patient with Down syndrome. 1640 56

Calcineurin (CaN) is a Ca(2+)- and calmodulin-dependent protein serine-threonine phosphatase that is thought to play an important role in the neuronal response to changes in the intracellular Ca(2+) concentration. CaN has been implicated in numerous physiological processes including learning and memory. Decreases in CaN expression are thought to be responsible for some of the pathological features seen in brain ischemia, Down's syndrome and Alzheimer's disease. In this study, we examined the possibility of CaN playing a role in the progressive neurological phenotype of the R6/2 mouse of Huntington's disease. We studied the effects of the CaN inhibitors cyclosporin A and FK506 on the progressive neurological phenotype in the R6/2 mouse. We found that an immunosuppressive dose of both drugs dramatically accelerated the main features of the neurological phenotype in R6/2 mice. This was unlikely to be due solely to the immunosuppressive action of these drugs, since treatment with cyclophosphamide, an immunosuppressant drug with a mechanism of action that is not mediated via CaN, did not have deleterious effects on the R6/2 mouse. If anything, cyclophosphamide improved the neurological symptoms in the R6/2 mice. Together, our data suggest a central role for CaN in the deleterious phenotype of the R6/2 mouse. Treatments aimed at preventing the loss of CaN or stimulating its function may be beneficial in the treatment of HD.
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PMID:Calcineurin inhibitors cause an acceleration of the neurological phenotype in a mouse transgenic for the human Huntington's disease mutation. 1671 37

Two hippocampal sectors show distinct responses to transient ischemia: the cornu Ammonis (CA)1 sector undergoes a delayed neuronal death followed by a lack of neuronal generation, while the dentate gyrus (DG) shows slight postischemic damage followed by an increased neurogenesis. Using the monkey experimental paradigm of transient whole brain global ischemia, the 'calpain-cathepsin hypothesis' was formulated in 1998. This hypothesis proposes that following ischemia calpain compromises the integrity of lysosomal membrane, causing a leakage of degrading hydrolytic enzymes--cathepsins--into the cytoplasm. Ischemia induces Ca(2+) mobilization, calpain activation, lysosomal membrane disruption, and cathepsin release, which all occur specifically in the CA1 sector and cause neuronal death. In the postischemic DG, a vascular niche has been implicated in adult neurogenesis, in that adventitial cells of the DG microvascular environment provoke postischemic up-reguation of neurogenesis with the aid of brain-derived neurotrophic factor and polysialylated form of the neural cell adhesion molecule. In parallel, Down's syndrome cell adhesion molecule has recently been shown to be expressed specifically in the neural progenitor cells of DG. In this review, we focus on the monkey experimental paradigm to reveal the remarkable contrasts between CA1 and DG in response to the ischemic insult.
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PMID:Differential response to ischemia in adjacent hippocampalsectors: neuronal death in CA1 versus neurogenesis in dentate gyrus. 1734 78

Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
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PMID:Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. 1737 2

Mitochondrial function in the brain of mouse trisomy 16, an animal model of Down syndrome with accelerated neuron death, was studied in isolated cortex mitochondria. Using an oxygen-sensitive Clarke electrode, a selective 16% decrease in respiration was detected with the Complex I substrates malate and glutamate but not with the Complex II substrate succinate. Western blotting revealed a 20% decrease in the 20 kDa subunit of Complex I in Ts16 brain cortex homogenates with no significant decrease in marker proteins for the other complexes of the electron transport chain. Although no differences in H(2)O(2) production or maximal calcium uptake were detected in the Ts16 mitochondria, there was an 18% decrease in pyruvate dehydrogenase levels, a change associated with oxidative stress in ischemia. These results are similar to those found in Parkinson's disease suggesting some neurodegenerative diseases may have mitochondrial pathology as a common step.
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PMID:Mitochondrial dysfunction in mouse trisomy 16 brain. 1806 Nov 51

S100B is a calcium-binding protein released by astroglial cells of the brain capable of producing numerous extracellular effects. Although the direct molecular mechanism remains unknown, these effects can be trophic including differentiation, growth, recovery, and survival of neurons when the S100B protein is mainly oxidized and neurotoxic including apoptosis and neuroinflammatory processes marked by microglial activation when in a reduced state. S100B and its receptor RAGE (receptor for advanced glycation end products) have been found to be increased in Alzheimer's disease, Down syndrome, with tissue trauma and ischemia. In the current study, we examined the binding of the S100B receptor (RAGE) on microglial cells and the developmental effects of the antioxidant vitamin E on microglial activation and the upregulation of RAGE in an S100B over-expressing mouse model of pathological aging. We report that RAGE is co-localized on activated microglial cells and vitamin E induced dramatic increases in microglial activation as well as total microglial relative optical density that was accompanied by upregulation of the RAGE receptor, particularly in the CA1 region of the hippocampus. Our findings suggest further investigation into the potential role of vitamin E in reducing the oxidation state of the S100B protein and its influence on neuroinflammatory processes marked by microglial activation in vivo.
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PMID:Vitamin E increases S100B-mediated microglial activation in an S100B-overexpressing mouse model of pathological aging. 1864 4

We report a patient with Down syndrome, under treatment with carbamazepine, levopromazine and clonazepam. After urinary infection he developed glans necrosis requiring excision of prepuce. Six hours post surgery he presented right-hand ischemia followed by arterial and venous thrombosis of the right thoracic extremity. Later, he progressed to a compartment syndrome and presented ischemia of toes. All the clinical manifestations developed over a week. Anticardiolipin (aCL) antibodies, lupus anticoagulant and perinuclear antineutrophil antibodies were positive. Anticoagulant and immunosuppressive treatment were initiated. Owing to the failure of both treatments, the patient underwent amputation of right hand and a toe. Histopathology revealed recent and old thrombosis of medium- and small-sized vessels without vasculitis. Diagnosis of catastrophic antiphospholipid syndrome (CAPS) was made. At present, the patient continues on oral anticoagulants, IgG aCL remains positive, and no further episodes of thromboses have been observed after 4 years of follow-up. To our knowledge, this is the first case of CAPS in a patient with Down syndrome.
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PMID:Catastrophic antiphospholipid syndrome in a patient with Down syndrome. 1976 87


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