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

The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in folding and processing membrane and secretory proteins. The importance of these reactions for normal cellular function is indicated by the fact that blocking of these processes is potentially lethal for cells. Under conditions associated with ER dysfunction, unfolded proteins accumulate in the ER lumen. This is the warning signal of two stress responses: the unfolded protein response (UPR) required for inducing the new synthesis of chaperons to refold the unfolded proteins, and the ER-associated degradation (ERAD) to degrade unfolded proteins at the proteasome. Cells in which UPR and ERAD cannot be activated to such an extent that ER function is restored die by apoptosis. In acute pathological states of the brain, including stroke, neurotrauma and epileptic seizures, and in degenerative diseases ER function is impaired in multiple ways. These include oxidative stress, nitric oxide-induced inactivation of the ER calcium pump resulting in disturbances of ER calcium homeostasis and impairment of UPR and ERAD. Furthermore, proteasomal function is impaired which causes secondary ER dysfunction. The only way to escape this potentially lethal cycle is to induce UPR and thus to activate new synthesis of ER chaperon GRP78 to levels sufficient to refold unfolded proteins. ER dysfunction may induce a state of tolerance, impair cellular functions, or induce apoptosis, depending on the severity and duration and the cell type affected. This review focuses on the possible role of ER dysfunction in the pathological process induced by transient cerebral ischemia.
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PMID:Endoplasmic reticulum dysfunction in brain pathology: critical role of protein synthesis. 1618 92

Obesity and insulin resistance are strongly associated with systemic markers of inflammation and endoplasmic reticulum stress. c-Jun N-terminal kinases (JNK) are activated by inflammatory cytokines and have a key role in beta-cell apoptosis and in negative regulation of insulin signaling. JNK1-deficient mice are protected from diet-induced obesity and insulin resistance, while genetically obese mice with targeted mutations in JNK1 are leaner and have reduced insulin and blood glucose levels. These studies validate JNK as a link between inflammation and metabolic diseases and as a promising drug target. This review highlights recent advances in small-molecule inhibitors of JNK that have also been targeted for other diseases with an inflammatory component such as stroke, rheumatoid arthritis, and Alzheimer's and Parkinson's diseases.
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PMID:JNK: bridging the insulin signaling and inflammatory pathway. 1625 18

Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress-inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways-the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress. In support of this theory, we demonstrate that glucosamine can induce ER stress in cell types relevant to the development of atherosclerosis, including human aortic smooth muscle cells, monocytes, and hepatocytes. Furthermore, we show that glucosamine-induced ER stress dysregulates lipid metabolism, leading to the accumulation of cholesterol in cultured cells. To examine the relevance of the ER stress pathway in vivo, we used a streptozotocin-induced hyperglycemic apolipoprotein E-deficient mouse model of atherosclerosis. Using molecular biological and histological techniques, we show that hyperglycemia is associated with tissue-specific ER stress, hepatic steatosis, and accelerated atherosclerosis. This novel mechanism may not only explain how diabetes and hyperglycemia promote atherosclerosis, but also provide a potential new target for therapeutic intervention.
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PMID:Glucosamine-induced endoplasmic reticulum dysfunction is associated with accelerated atherosclerosis in a hyperglycemic mouse model. 1638 Apr 81

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. The cellular regulation of glutamate receptor (GluR) ion channel function and expression is important for maintaining or adjusting target cell excitability to meet ever-changing demands, for example, in relation to developmental or use-dependent synaptic plasticity. Dysregulation of GluR function or expression may be a contributing factor in certain forms of epilepsy, stroke/ischemia, head trauma, cognitive impairments, and neurodegenerative disease. Recent years have seen substantial progress in understanding how GluRs operate in terms of their structural and functional properties, their synaptic targeting and membrane anchoring by PDZ-domain proteins, and their activity-dependent cycling at the plasma membrane. Yet precious little is known about the earliest events in GluR biogenesis or the mechanisms in place to ensure the GluRs that reach the cell surface are processed, folded, and oligomerized in an appropriate manner. Indeed, only a minor fraction of the GluR content of cells is expressed at any given time on the cell surface, whereas most of the remaining receptors exist in the endoplasmic reticulum (ER). The functional competence and significance of the ER fraction of receptors are presently unknown, but they are generally thought to represent immature, unassembled, or improperly assembled subunits. Some are ultimately destined for insertion in the plasma membrane. Others may be targeted for proteosomal degradation. Still others might provide a latent pool of fully functional receptors that can be recruited to enhance cell excitability in response to specific signals or under pathological conditions. This review will explore the structural and functional elements that regulate GluR assembly and export from the ER.
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PMID:Glutamate receptors and endoplasmic reticulum quality control: looking beneath the surface. 1668 68

Bax ihibitor-1 (BI-1) has been characterized as an inhibitor of Bax-induced cell death in plants and various mammalian cell systems. To explore the function of BI-1 in neurons, we overexpressed BI-1 tagged to HA or GFP in rat nigral CSM14.1 and human SH-SY5Y neuroblastoma cells. Stable BI-1 expression proved marked protection from cell death induced by thapsigargine, a stress agent blocking the Ca2+-ATPase of the endoplasmic reticulum (ER) but failed to inhibit cell death induced by staurosporine, a kinase inhibitor initiating mitochondria-dependent apoptosis. Moreover, BI-1 was neuroprotective in a paradigm mimicking ischemia, namely oxygen-glucose as well as serum deprivation. Examination of the subcellular distribution revealed that BI-1 predominantly locates to the ER and nuclear envelope but not mitochondria. Taken together, BI-1 overexpression in the ER is protective in neurons, making BI-1 an interesting target for future studies aiming at the inhibition of neuronal cell death during neurodegenerative diseases and stroke.
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PMID:Bax inhibitor-1 protects neurons from oxygen-glucose deprivation. 1675 4

There are many similarities in molecular mechanisms of neuronal cell death observed in ischemic stroke and Alzheimer's disease. From point of organelle damage, we introduced molecular events seen in ischemic stroke, and compared the findings with that observed in Alzheimer's disease. In the brain after ischemia, transmembrane potential and ion gradient are disturbed at very early stage. Several drugs are aimed to minimize this change, some of which were effective in experimental models. Calcium blocker and glutamate antagonist were also effective for Alzheimer's disease. As for mitochondrial and endoplasmic reticulum damage, both disorders share common pathological findings such as pro-apoptotic signals activation. However, there are some molecules which are neuroprotective in Alzheimer's disease but pro-apoptotic in ischemic neurons. We need to be so careful for judging the significance of a phenomenon obtained by an experiment. Lysosome, called as suicide bag, play important roles both in the brain of ischemic stroke and Alzheimer's disease. Leak of lysosomal enzymes influence, at least partially, the fate of neurons under pathological conditions in both disorders.
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PMID:Molecular mechanisms of ischemic neuronal cell death--with relevance to Alzheimer's disease. 1701 65

Several studies have suggested that a potential mechanism for estrogen-mediated neuroprotection following experimental stroke is a result of modulating glutamate-mediated excitotoxicity. Our laboratory has shown that in male rats, estrogen injection (systemic or direct intracortical injection) resulted in an immediate depolarization of cortical neurons. Therefore, the present study was designed to investigate whether the estrogen-induced depolarization of cortical neurons was required in mediating the early events associated with this neuroprotection. We tested this hypothesis by co-injecting selective antagonists of the NMDA (MK-801) or AMPA (DNQX) glutamatergic receptors with estrogen. Systemic injection of estrogen significantly attenuated the MK-801-induced decrease in infarct volume following middle cerebral artery occlusion (MCAO). Similarly, when estrogen and MK-801 were co-injected directly into the cortex, no neuroprotection was observed. However, when estrogen or MK-801 was injected centrally 10 min prior to the injection of the other drug, significant neuroprotection was observed. This led us to hypothesize that estrogen-mediated neuroprotection required an initial activation of NMDA receptors. Furthermore, our results suggest that this estrogen-mediated neuroprotection was also associated with a significant increase in m-calpain and activation of an endoplasmic reticulum (ER) specific caspase-12. Finally, the results of current clamp experiments showed that estrogen significantly depolarized cortical neurons as well as enhanced NMDA-induced depolarization. Taken together, these results suggest that estrogen pretreatment may activate NMDA receptors resulting in modification of ER-associated molecular mechanisms involved in neuroprotection following MCAO.
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PMID:Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation. 1731 17

When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
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PMID:Calcium and neurodegeneration. 1732 89

The purpose of this study was to compare the morphological changes in the focus of ischemic stroke under the influence of the drugs of neurotrophic group (alpha-GPC, cerebrolysin), drugs possessing the nootropic properties (piracetam) and those with combined effect (vinpocetin). The experiments were performed in 18 rats. Temporary disturbance of cerebral circulation (acute ischemia) in right cerebral hemisphere was induced by clipping the trunk of innominate artery for 40 minutes. Areas of cerebral cortex, brainstem and cerebellar cortex were studied using light and electron microscopy. Treatment with alpha-GPC or cerebrolysin resulted in an increased tolerance of neurons to ischemic damage and in delayed realization of the program of cell death. Some intracellular changes were detected that could be regarded as the signs of adaptation and repair (indentation of nuclear envelope, increased number of ribosomes, hypertrophy of endoplasmic reticulum and Golgi complex). These drugs preserved the structure of the membranes in the nucleus and major organelles. In animals treated with piracetam and vinpocetin, all morphological signs were indicative of insufficient supply of energy-consuming processes of repair in the acute phase of ischemic stroke. This was accompanied by morphological features of functional stress of the neurons of the cerebral cortex, different stages of gliocyte apoptosis, phenomenon of incomplete separation of gliocytes during their proliferation, myelin and unmyelinated nerve fiber pathology, as well as by changes in synapse structure.
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PMID:[Changes in the focus of experimental ischemic stroke under the influence of neuroprotective drugs]. 1733 15

Estrogen has received considerable attention as a potential therapeutic agent against various forms of neurodegenerative diseases including stroke. Experimental data in animal models of stroke have provided exhaustive evidence of the neuroprotective properties of this steroid hormone. Our laboratory in particular has demonstrated that acute estrogen treatment in male rats significantly reduced (approximately 50%) ischemic cell death within 4 h following permanent occlusion of the middle cerebral artery occlusion (MCAO). However, the cellular and molecular mechanisms implicated in the protective actions of estrogen in this experimental model have yet to be elucidated. Accumulating evidence suggests that in various in vivo and in vitro models, estrogen can be pro-apoptotic and that this effect may be mediated by an estrogen-induced up-regulation of the Fas/FasL system and the subsequent activation of caspase-12. We therefore hypothesized that under ischemic conditions following MCAO, estrogen would up-regulate protective endoplasmic reticulum (ER) stress pathways leading to caspase-12 activation, thus limiting infarct volume. Our results showed that estrogen significantly increased activated caspase-12 at 2, 3 and 4 h post-MCAO. Immunostaining of brain sections showed a significantly higher number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling positive cells in estrogen-treated animals at 4 h, but not at 2 h, post-MCAO. These findings correlate with previous observations that differences in infarct volume between saline and estrogen-treated animals are not seen until 3 and 4 h post-MCAO. A decrease in m-calpain expression was observed in the infarct region only at 4 h post-MCAO following estrogen pre-treatment, suggesting m-calpain may not be involved in regulating estrogen-induced caspase-12 activation. Based on these cellular changes correlated to estrogen pretreatment, we conclude that estrogen may up-regulate ER-specific apoptotic pathways, thus limiting the extent of necrotic cell death which is responsible for the spreading depression and growth of the infarct volume following MCAO.
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PMID:Estrogen limits ischemic cell death by modulating caspase-12-mediated apoptotic pathways following middle cerebral artery occlusion. 1743 54


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