UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that excitotoxicity may contribute to neuronal damage in neurodegenerative diseases including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. Activated microglia have been observed around degenerative neurons in these diseases, and they are thought to act as effector cells in the degeneration of neural cells in the central nervous system. Neuritic beading, focal bead-like swellings in the dendrites and axons, is a neuropathological sign in epilepsy, trauma, ischemia, aging, and neurodegenerative diseases. Previous reports showed that neuritic beading is induced by various stimuli including glutamate or nitric oxide and is a neuronal response to harmful stimuli. However, the precise physiologic significance of neuritic beading is unclear. We provide evidence that neuritic beading induced by activated microglia is a feature of neuronal cell dysfunction toward neuronal death, and the neurotoxicity of activated microglia is mediated through N-methyl-d-aspartate (NMDA) receptor signaling. Neuritic beading occurred concordant with a rapid drop in intracellular ATP levels and preceded neuronal death. The actual neurite beads consisted of collapsed cytoskeletal proteins and motor proteins arising from impaired neuronal transport secondary to cellular energy loss. The drop in intracellular ATP levels was because of the inhibition of mitochondrial respiratory chain complex IV activity downstream of NMDA receptor signaling. Blockage of NMDA receptors nearly completely abrogated mitochondrial dysfunction and neurotoxicity. Thus, neuritic beading induced by activated microglia occurs through NMDA receptor signaling and represents neuronal cell dysfunction preceding neuronal death. Blockage of NMDA receptors may be an effective therapeutic approach for neurodegenerative diseases.
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PMID:Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. 1564 Jan 50

Neural membrane phospholipids are hydrolyzed by a group of enzymes known as phospholipases. This process results in the generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor, and diacylglycerols. High levels of these metabolites are neurotoxic and are associated with neurodegeneration. The collective evidence from many studies suggests that neural membrane phospholipid metabolism is disturbed in neural trauma and neurodegenerative diseases. This disturbance is caused by the stimulation of phospholipases A2. Stimulation of these enzymes produces changes in membrane permeability, fluidity, and alteration in ion homeostasis. Low calcium influx produces mild oxidative stress and results in neurodegeneration promoted by apoptosis, whereas a calcium overload generates high oxidative stress and causes neurodegeneration associated with necrosis. Alterations in phospholipid metabolism along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for neurodegeneration in ischemia, spinal cord trauma, head injury, and Alzheimer disease. The synthesis of phospholipases A2 inhibitors that cross the blood-brain barrier without harm may be useful for the treatment of acute neural trauma and neurodegenerative diseases.
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PMID:Biochemical aspects of neurodegeneration in human brain: involvement of neural membrane phospholipids and phospholipases A2. 1566 32

We previously demonstrated that pharmacological inhibition of Na(+)-K(+)-Cl- cotransporter isoform 1 (NKCC1) is neuroprotective in in vivo and in vitro ischemic models. In this study, we investigated whether genetic ablation of NKCC1 provides neuroprotection after ischemia. Focal ischemia was induced by 2 hours occlusion of the left middle cerebral artery (MCAO) followed by 10 or 24 hours reperfusion. Two hours MCAO and ten or twenty-four hours reperfusion caused infarction (approximately 85 mm3) in NKCC1 wild-type (NKCC1(+/+)) mice. Infarction volume in NKCC1(-/-) mice was reduced by approximately 30% to 46%. Heterozygous mutant (NKCC1(+/-)) mice showed approximately 28% reduction in infarction (P>0.05). Two hours MCAO and twenty-four hours reperfusion led to a significant increase in brain edema in NKCC1(+/+) mice. In contrast, NKCC1(+/-) and NKCC1(-/-) mice exhibited approximately 50% less edema (P<0.05). Moreover, white matter damage was assessed by immunostaining of amyloid precursor protein (APP). An increase in APP was detected in NKCC1(+/+) mice after 2 hours MCAO and 10 hours reperfusion. However, NKCC1(-/-) mice exhibited significantly less APP accumulation (P<0.05). Oxygen-glucose deprivation (OGD) induced approximately 67% cell death and a fourfold increase in Na+ accumulation in cultured NKCC1(+/+) cortical neurons. OGD-mediated cell death and Na+ influx were significantly reduced in NKCC1(-/-) neurons (P<0.05). In addition, inhibition of NKCC1 by bumetanide resulted in similar protection in NKCC1(+/+) neurons and astrocytes (P<0.05). These results imply that stimulation of NKCC1 activity is important in ischemic neuronal damage.
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PMID:Na(+)-dependent chloride transporter (NKCC1)-null mice exhibit less gray and white matter damage after focal cerebral ischemia. 1567 12

The levels of amyloid beta-peptides (Abeta) in the brain represent a dynamic equilibrium state as a result of their biosynthesis from the amyloid precursor protein (APP) by beta- and gamma-secretases, their degradation by a team of amyloid-degrading enzymes, their subsequent oligomerization, and deposition into senile plaques. While most therapeutic attention has focused on developing inhibitors of secretases to prevent Abeta formation, enhancing the rate of Abeta degradation represents an alternative and viable strategy. Current evidence both in vivo and in vitro suggests that there are three major players in amyloid turnover: neprilysin, endothelin converting enzyme(s), and insulin-degrading enzyme, all of which are zinc metallopeptidases. Other proteases have also been implicated in amyloid metabolism, including angiotensin-converting enzyme, and plasmin but for these the evidence is less compelling. Neprilysin and endothelin converting enzyme(s) are homologous membrane proteins of the M13 peptidase family, which normally play roles in the biosynthesis and/or metabolism of regulatory peptides. Insulin-degrading enzyme is structurally and mechanistically distinct. The regional, cellular, and subcellular localizations of these enzymes differ, providing an efficient and diverse mechanism for protecting the brain against the normal accumulation of toxic Abeta peptides. Reduction in expression levels of some of these proteases following insults (e.g., hypoxia and ischemia) or aging might predispose to the development of Alzheimer's disease. Conversely, enhancement of their levels by gene delivery or pharmacological means could be neuroprotective. Even a relatively small enhancement of Abeta metabolism could slow the inexorable progression of the disease. The relative merits of targeting these enzymes for the treatment of Alzheimer's disease will be reviewed and possible side-effects of enhancing their activity evaluated.
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PMID:Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration. 1568 97

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.
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PMID:Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes. 1568 98

We quantitatively assessed both gray and white matter injury after spinal cord ischemia in rats, and the relationship between the magnitude of gray and white matter injury was determined. Twenty-five male rats were anesthetized with isoflurane, and spinal cord ischemia (SCI) was induced by balloon intraaortic occlusion combined with hypotension. The animals were randomly allocated to one of the following three groups: animals with SCI for 12 min (SCI-12; n = 8), 15 min (SCI-15; n = 9), or those with sham operation (n = 8). Twenty-four hours after reperfusion, hindlimb motor function was assessed using the Basso-Beattie-Bresnahan scale scoring. Gray matter damage was assessed on the basis of the number of normal neurons in the ventral horn. White matter damage was assessed on the basis of the extent of vacuolation and amyloid precursor protein immunoreactivity in the ventral and ventrolateral white matter. There were significantly less normal neurons in the SCI-15 group compared with those in the SCI-12 and sham groups (P < 0.05). There was a significant positive correlation between the Basso-Beattie-Bresnahan scores and the number of normal neurons. The percentages of vacuolation areas in the SCI-15 group were significantly larger compared with those in the SCI-12 and sham groups (30% +/- 10% versus 9% +/- 7%, 0% +/- 0%, P < 0.05). Immunohistochemical analysis revealed increased amyloid precursor protein immunoreactivity in the swollen axons, especially in the SCI-15 group. There was a significant negative correlation between the number of normal neurons and percentages of vacuolation areas. These results indicate that both gray and white matter were injured after SCI in rats and the degree of white mater injury was correlated with the severity of gray matter injury after a relatively short recovery period.
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PMID:An evaluation of white matter injury after spinal cord ischemia in rats: a comparison with gray matter injury. 1572 78

Moderate focal brain hypoxic-ischemic (HI) injury in the immature P3 rat leads to loss of cortical volume and disruptions of cortical myelination. In this study, we characterized the time course and pattern of cellular degeneration, axonal disruption, astrogliosis, and microglia activation. After moderate transient unilateral hypoxia-ischemia, brains were collected at set time points and positive staining was assessed. Cellular degeneration stained with Fluoro-Jade B (FJ-B) was distributed in a columnar pattern, primarily within the deep cortical layers V-VII extending up to layer IV of the parietal cortex (pCx). FJ-B staining increased in the ipsilateral pCx 12 and 24 h (p < 0.05) after the injury. Beta-amyloid precursor protein immunoreactivity indicating axonal disruption increased at 24 h (p < 0.05) and showed the same distribution as FJ-B. Glial fibrillary acidic protein-positive astrocytes increased dramatically within the ipsilateral pCx from 24 h (p < 0.05) to 18 d (p < 0.001) after HI injury and displayed a columnar pattern extending from the deep cortical layers to layers IV. Isolectin-B4 and ED1-labeled microglia were also increased within the ipsilateral deep pCx and underlying white matter between 12 and 24 h (p < 0.01), and increased Isolectin-B4 lasted up to 7 d after injury. These observations are consistent with the hypothesis that neuronal loss, astrogliosis, and microglia activation precede the subsequent disruption of cortical growth and myelination. This model offers new possibilities for investigating the cellular and molecular mechanisms of damage and repair after neonatal HI injury.
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PMID:Distinctive neuropathologic alterations in the deep layers of the parietal cortex after moderate ischemic-hypoxic injury in the P3 immature rat brain. 1577 44

Progressive memory impairment, beta-amyloid (Abeta) plaques associated with local inflammation, neurofibrillary tangles, and loss of neurons in selective brain areas are hallmarks of Alzheimer's disease (AD). Although beta-amyloid precursor protein (APP) and Abeta have a central role in the etiology of AD, it is not clear which forms of APP or Abeta are responsible for the neuronal vulnerability in AD brain. Brain ischemia, another cause of dementia in the elderly, has recently been recognized to contribute to the pathogenesis of AD and individuals with severe cognitive decline and possibly underlying AD are at increased risk for ischemic events in the brain. Moreover, the epsilon4 allele of apolipoprotein E (ApoE) is a risk factor for both AD and poor outcome following brain ischemia and hemorrhage. Several factors and molecular mechanisms that lower the threshold of neuronal death in models of AD have recently been described. Among these neuroinflammation seems to play an important role. The development and maturation of both AD neuropathology and ischemic lesions in the central nervous system are characterized by activation of glial cells and upregulation of inflammatory mediators. Indeed, anti-inflammatory approaches have proven to be beneficial in the prevention and treatment of AD-like neuropathology and ischemic injuries in vivo. This review summarizes some of the findings suggesting that neuronal overexpression of human APP renders the brain more vulnerable to ischemic injury and describes the factors that are involved in increased neuronal susceptibility to ischemic stroke.
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PMID:Interactions between Alzheimer's disease and cerebral ischemia--focus on inflammation. 1585 Jun 63

The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.
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PMID:Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. 1585 Jun 77

The biosynthesis of oxygenated arachidonic acid messengers triggered by cerebral ischemia-reperfusion is preceded by an early and rapid phospholipase A2 activation reflected in free arachidonic and docosahexaenoic acid (DHA) accumulation. These fatty acids are released from membrane phospholipids. Both fatty acids are derived from dietary essential fatty acids; however, only DHA, the omega-3 polyunsaturated fatty acyl chain, is concentrated in phospholipids of various cells of brain and retina. Synaptic membranes and photoreceptors share the highest content of DHA of all cell membranes. DHA is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling, and has been implicated in neuroprotection. In addition, this fatty acid is required for retinal pigment epithelium cell (RPE) functional integrity. Here we provide an overview of the recent elucidation of a specific mediator generated from DHA that contributes at least in part to its biological significance. In oxidative stress-challenged human RPE cells and rat brain undergoing ischemia-reperfusion, 10,17S-docosatriene (neuroprotectin D1, NPD1) synthesis evolves. In addition, calcium ionophore A23187, IL-1beta, or the supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous free DHA followed by NPD1 formation occurs, suggesting that a phospholipase A2 releases the mediator's precursor. When NPD1 is infused during ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA damage is down-regulated. NPD1 also up-regulates the anti-apoptotic Bcl-2 proteins Bcl-2 and BclxL and decreases pro-apoptotic Bax and Bad expression. Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also inhibits IL-1beta-stimulated expression of COX-2. Overall, NPD1 protects cells from oxidative stress-induced apoptosis. Because photoreceptors are progressively impaired after RPE cell damage in retinal degenerative diseases, understanding of how these signals contribute to retinal cell survival may lead to the development of new therapeutic strategies. Moreover, NPD1 bioactivity demonstrates that DHA is not only a target of lipid peroxidation, but rather is the precursor to a neuroprotective signaling response to ischemia-reperfusion, thus opening newer avenues of therapeutic exploration in stroke, neurotrauma, spinal cord injury, and neurodegenerative diseases, such as Alzheimer disease, aiming to up-regulate this novel cell-survival signaling.
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PMID:Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. 1591 89

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