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)

We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wild-type (WT) mice in three age groups: 3-4 wk, before the overt behavioral phenotype develops; 5-9 wk, as overt behavioral symptoms begin; and 10-15 wk when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3-4 wk WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively; at 5-9 and 10-15 wk, responses recovered more slowly from OGD. In contrast, although 3-4 wk R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5-9 and 10-15 wk. As a result, a "crossover" point occurred, roughly coinciding with the development of the overt behavioral phenotype (5-9 wk), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3-4 wk R6/2 responses was not due to excessive glutamate release during OGD as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1 mM). Although the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.
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PMID:Age-dependent biphasic changes in ischemic sensitivity in the striatum of Huntington's disease R6/2 transgenic mice. 1537 92

Oxidative stress plays an important role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Animal models of PD or HD, produced by administration of the mitochondrial toxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 3-nitropropionic acid (3NP), respectively, show increased free radical generation. Free radicals generated in biological systems can react with spin-trapping compounds, such as nitrones, to form stable adducts. In recent years, the utility of nitrones has moved beyond analytical applications and into the realm of neuroprotection as antioxidants in both brain ischemia and models of neurodegenerative diseases. In the present study, we administered a new nitrone antioxidant, stilbazulenyl nitrone (STAZN), with either MPTP or 3NP. STAZN attenuated MPTP-induced striatal dopamine depletion by 40% and showed a tendency to dose-dependent neuroprotection. STAZN dose-dependently protected against loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. STAZN reduced the striatal lesion volume caused by systemic 3NP administration from 44 +/- 9 to 20 +/- 6 mm(3). The lipid peroxidation marker, malondialdehyde(MDA), was significantly increased in the striatum, cortex, and cerebellum of rats after administration of 3NP. These increases were blocked by co-injection of STAZN. Our data provide further evidence that STAZN is a neuroprotective free radical spin trap, and suggest that the development of new antioxidants will broaden our therapeutic strategies for neurodegenerative diseases.
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PMID:A novel azulenyl nitrone antioxidant protects against MPTP and 3-nitropropionic acid neurotoxicities. 1558 15

It is thought that the combination of extracellular glutamate accumulation and mitochondrial damage is involved in neuronal death associated with brain ischemia and hypoglycemia, and some neurodegenerative diseases such as Huntington's disease. However, the mechanism whereby those two factors interact together to trigger neurodegeneration in this and other neurodegenerative disorders is still elusive. Here, we have addressed this issue using a model of mild and sustained accumulation of extracellular glutamate in cerebellar cultured neurons, which are mostly glutamatergic and commonly used to study glutamate neurotoxicity. The resulting stimulation of glutamate receptors triggered a approximately 50% persistent increase in mitochondrial respiration that was associated with free radicals formation, and which was found to be necessary to prevent the collapse of the mitochondrial membrane potential (Deltapsim) and apoptotic cell death. In fact, hampering the glutamate-mediated increase in mitochondrial respiration with an inhibitor of the mitochondrial respiratory chain stopped neurons from producing free radicals, but led them to undergo rapid and profound Deltapsim collapse and apoptotic cell death. Thus, we suggest that the formation of reactive oxygen species by glutamate receptor activation is the unavoidable consequence of an increase in the mitochondrial respiration aimed to prevent Deltapsim collapse and neurodegeneration. These results may be relevant to understand the pathophysiology of those neurodegenerative diseases associated with both mitochondrial respiratory chain and glutamate transporter defects.
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PMID:Increased mitochondrial respiration maintains the mitochondrial membrane potential and promotes survival of cerebellar neurons in an endogenous model of glutamate receptor activation. 1560 7

Neurodegenerative diseases such as Huntington's disease, ischemia, and Alzheimer's disease (AD) are major causes of death. Recently, metabotropic glutamate receptors (mGluRs), a group of seven-transmembrane-domain proteins that couple to G-proteins, have become of interest for studies of pathogenesis. Group I mGluRs control the levels of second messengers such as inositol 1,4,5-triphosphate (IP3), Ca2+ ions and cAMP. They elicit the release of arachidonic acid via intracellular Ca2+ mobilization from intracellular stores such as mitochondria and endoplasmic reticulum. This facilitates the release of glutamate and could trigger the formation of neurofibrillary tangles, a pathological hallmark of AD. mGluRs regulate neuronal injury and survival, possibly through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrially mediated programmed cell death. They may also play a role in glutamate-induced neuronal death by facilitating Ca(II) mobilization. Hence, mGluRs have become a target for neuroprotective drug development. They represent a pharmacological path to a relatively subtle amelioration of neurotoxicity because they serve a modulatory rather than a direct role in excitatory glutamatergic transmission.
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PMID:The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in Alzheimer's disease. 1563 4

3-Nitropropionic acid (3-NPA) is a suicide inactivator of succinate dehydrogenase (SDH), commonly used as a pharmacological model of Huntington's disease in rodents. Several studies have shown that a single administration of 3-NPA given systemically provides subsequent ischemic tolerance. The present study has tested the hypothesis that 3-NPA is capable of inducing tolerance in a model of permanent focal cerebral ischemia and whether 3-NPA can be truly applicable as a tolerance-inducer to ischemia. Rats given 3-NPA intraperitoneally revealed that the mortality of 3-NPA of 15, 20, and 25 mg/kg groups was 20.5, 38.8, and 83.3%, respectively. All rats survived without behavioral sequelae at smaller doses. Three days after 3-NPA preconditioning, the rats showing no behavioral changes underwent the permanent middle cerebral artery occlusion. The groups treated with 10 and 15 mg/kg of 3-NPA showed significantly reduced neurological deficits and infarction volumes in comparison with the control group, whereas the groups treated with 5 and 20 mg/kg of 3-NPA revealed no tolerance effects. When the regional SDH activity (% of control) was photometrically semi-quantified, it was observed that the activity was reduced to 90.8, 76.1, 67.8, and 64.3% in the outer layers of the cerebral cortex, and to 79.4, 67.5, 63.2, and 62.9% in the striatum 1 h after 3-NPA application (5, 10, 15, 20 mg/kg), respectively. In conclusion, although the preconditioning with 3-NPA is clearly shown in the setting of permanent ischemia, the preconditioning with this mitochondrial toxin demonstrated a rather narrow safety margin (critical threshold).
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PMID:The critical threshold of 3-nitropropionic acid-induced ischemic tolerance in the rat. 1596 Oct 68

The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in calcium storage and signaling. Disturbances of ER calcium homeostasis constitute a severe form of stress interfering with central functions of this structure including the folding and processing of newly synthesized membrane and secretory proteins. Blocking the folding and processing reactions results in the accumulation of unfolded proteins forming potentially toxic aggregates. To restore ER functioning, specific stress responses are activated one of which is the unfolded protein response (UPR). UPR is characterized by a shutdown of global protein synthesis and activation of expression of genes coding for ER-resident proteins that are involved in the folding and processing reactions. ER calcium homeostasis is therefore inevitably associated with major cellular functions, including gene transcription and translation. ER calcium homeostasis und ER functions are believed to be impaired in various degenerative diseases of the brain including Alzheimer's, Parkinson's and Huntington's disease, and amyotrophic lateral sclerosis. ER functioning has also been shown to be disturbed in acute pathological states of the brain such as ischemia and trauma, which have been identified as risk factors for the development of degenerative diseases. This implies that there are common underlying pathomechanisms. This review will summarize new observations suggesting that impairment of ER functioning may be a common denominator of pathological processes resulting in neuronal cell injury in acute disorders and degenerative diseases of the brain.
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PMID:Endoplasmic reticulum stress response and neurodegeneration. 1608 31

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neuropeptides in the mammalian central nervous system (CNS). An overview of the distribution of the G-protein coupled NPY receptor family (Y(1), Y(2), Y(4), Y(5) receptors) in the brain is described. The coexistence of NPY with other neurotransmitters and its wide distribution in several brain areas predict the high importance of NPY as a neuromodulator. Thus, the effect of NPY on the release of several neurotransmitters such as glutamate, gamma-aminobutyric acid (GABA), norepinephrine (NE), dopamine, somastotatin (SOM), serotonin (5-HT), nitric oxide (NO), growth hormone (GH) and corticotropin releasing factor (CRF) is reviewed. A neuroprotective role for NPY under physiological conditions and during hyperactivity such as epileptic-seizures has been suggested. We have shown previously that NPY inhibits glutamate release evoked from hippocampal nerve terminals and has a neuroprotective effect in rat organotypic hippocampal cultures exposed to an excitotoxic insult. Moreover, changes in NPY levels have been observed in different pathological conditions such as brain ischemia and neurodegenerative diseases (Huntington's, Alzheimer's and Parkinson's diseases). Taken together, these studies suggest that NPY and NPY receptors may represent pharmacological targets in different pathophysiological conditions in the CNS.
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PMID:The putative neuroprotective role of neuropeptide Y in the central nervous system. 1610 53

Unfolded proteins accumulate in the lumen of the endoplasmic reticulum (ER) as part of the cellular response to cerebral hypoxia/ischemia and also to the overexpression of the mutant genes responsible for familial forms of degenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyothrophic lateral sclerosis, and Huntington's disease, as well as other disorders that are caused by an expanded CAG repeat. This accumulation arises from an imbalance between the load of proteins that need to be folded and processed in the ER lumen and the ER folding/processing capacity. To withstand such potentially lethal conditions, stress responses are activated that includes the shutdown of translation to reduce the ER work load and the activation of the expression of genes coding for proteins involved in the folding and processing reactions, to increase folding/processing capacity. In transient cerebral ischemia, ER stress-induced suppression of protein synthesis is believed to be too severe to permit sufficient activation of the genetic arm of the ER stress response. Mutations associated with Alzheimer's disease down-regulate the ER stress response and make cells more vulnerable to conditions associated with ER stress. When the functioning of the ER is severely impaired and affected cells can no longer withstand these stressful conditions, programmed cell death is induced, including a mitochondria-driven apoptotic pathway. Raising the resistance of cells to conditions that interfere with ER functions and activating the degradation and refolding of unfolded proteins accumulated in the ER lumen are possible strategies for blocking the pathological process leading to cell death at an early stage.
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PMID:Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease--therapeutic potential. 1614 Mar 87

Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.
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PMID:The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. 1617 24

Experimental and clinical studies support the view that the semisynthetic tetracycline minocycline exhibits neuroprotective roles in several models of neurodegenerative diseases, including ischemia, Huntington, Parkinson diseases, and amyotrophic lateral sclerosis. However, recent evidence indicates that minocycline does not always present beneficial actions. For instance, in an in vivo model of Huntington's disease, it fails to afford protection after malonate intrastriatal injection. Moreover, it reverses the neuroprotective effect of creatine in nigrostriatal dopaminergic neurons. This apparent contradiction prompted us to analyze the effect of this antibiotic on malonate-induced cell death. We show that, in rat cerebellar granular cells, the succinate dehydrogenase inhibitor malonate induces cell death in a concentration-dependent manner. By using DFCA, monochlorobimane and 10-N-nonyl-Acridin Orange to measure, respectively, H2O2-derived oxidant species and reduced forms of GSH and cardiolipin, we observed that malonate induced reactive oxygen species (ROS) production to an extent that surpasses the antioxidant defense capacity of the cells, resulting in GSH depletion and cardiolipin oxidation. The pre-treatment for 4 h with minocycline (10-100 microM) did not present cytoprotective actions. Moreover, minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin. Additional experiments revealed that minocycline was also unsuccessful to prevent the mitochondrial swelling induced by malonate. Furthermore, malonate did not induce the expression of the iNOS, caspase-3, -8, and -9 genes which have been shown to be up-regulated in several models where minocycline resulted cytoprotective. In addition, malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline, controversially the mechanism previously proposed to explain minocycline protective action. These results suggest that the minocycline protection observed in several neurodegenerative disease models is selective, since it is absent from cultured cerebellar granular cells challenged with malonate.
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PMID:Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death. 1624 43


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