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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress-induced activation of the expression of the endoplasmic reticulum (ER)-resident chaperon and member of the protein disulfide isomerase family erp72 was studied after transient cerebral ischemia in vivo using the four-vessel occlusion method and experimental depletion of ER calcium stores in primary neuronal cell cultures. After 8 days in vitro, neurons were exposed to thapsigargin (Tg), an irreversible inhibitor of ER Ca2+-ATPase, or the Tg solvent DMSO. In separate experiments neurons were pre-loaded with the cell-permeant calcium chelator BAPTA-AM before Tg exposure. Stress-induced changes in erp72 expression were analysed by quantitative PCR. Transient cerebral ischemia produced a significant increase in erp72 mRNA levels which rose to about 200% of control (hippocampus) or 300% of control (cortex). After depletion of ER calcium stores neuronal erp72 mRNA levels rose markedly, peaking at 12 h of recovery. Counteracting the Tg-induced rise in cytoplasmic calcium activity by preloading cells with the chelator BAPTA-AM did not influence erp72 expression significantly, suggesting that the activation of erp72 expression resulted from the depletion of ER calcium stores and not from the corresponding increase in cytoplasmic calcium activity. An activation of erp72 expression is indicative of a disturbance of ER function. The results of the present study therefore provide evidence to support the notion that transient cerebral ischemia induces disturbances of neuronal ER function, probably through a depletion of ER calcium stores.
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PMID:Erp72 expression activated by transient cerebral ischemia or disturbance of neuronal endoplasmic reticulum calcium stores. 957 Jun 40

The expression of the gene encoding the C/EBP-homologous protein (CHOP), which is also known as growth arrest and DNA-damage-inducible gene 153 (gadd153), has been shown to be specifically activated under conditions that disturb the functioning of the endoplasmic reticulum (ER). To investigate a possible role of ER dysfunction in the pathological process of ischemic cell damage, we studied ischemia-induced changes in gadd153 expression using quantitative PCR. Transient cerebral ischemia was produced in rats by four-vessel occlusion. In the hippocampus, ischemia induced a pronounced increase in gadd153 mRNA levels, peaking at 8 h of recovery (6.4-fold increase, p<0.01), whereas changes in the cortex were less marked (non-significant increase). To elucidate the possible mechanism underlying this activation process, gadd153 mRNA levels were also evaluated in primary neuronal cell cultures under two different conditions, both leading to a depletion of ER calcium pools in the presence or absence of an increase in cytoplasmic calcium activity. The first procedure, exposure to thapsigargin, an irreversible inhibitor of ER Ca2+-ATPase, caused a marked increase in gadd153 mRNA levels both in cortical and hippocampal neurons, peaking at 12-18 h after treatment. The second procedure, immersion of cells in calcium free medium supplemented with EGTA, caused only a transient increase in gadd153 mRNA levels, peaking at 6 h of recovery, indicating that a depletion of ER calcium stores in the absence of an increase in cytoplasmic calcium activity is sufficient to activate neuronal gadd153 expression. The results imply that transient cerebral ischemia disturbs the functioning of the ER and that these pathological changes are more pronounced in the hippocampus compared to the cortex.
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PMID:Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. 974 29

Rilmenidine, a ligand for imidazoline and alpha2-adrenergic receptors, is neuroprotective following focal cerebral ischemia. We investigated the effects of rilmenidine on cytosolic free Ca2+ concentration ([Ca2+]i) in rat astrocytes. Rilmenidine caused concentration-dependent elevation of [Ca2+]i, consisting of a transient increase (1-100 microM rilmenidine) or a transient increase followed by sustained elevation above basal levels (1-10 mM rilmenidine). A similar elevation in [Ca2+]i was induced by the imidazoline ligand cirazoline. The transient response to rilmenidine was observed in Ca2+-free medium, indicating that rilmenidine evokes release of Ca2+ from intracellular stores. However, the sustained elevation of Ca2+ was completely dependent on extracellular Ca2+, consistent with rilmenidine activating Ca2+ influx. Pretreatment with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, abolished the response to rilmenidine, confirming the involvement of intracellular stores and suggesting that rilmenidine and thapsigargin activate a common Ca2+ influx pathway. The alpha2-adrenergic antagonist rauwolscine attenuated the increase in [Ca2+]i induced by clonidine (a selective alpha2 agonist), but not the response to rilmenidine. These results indicate that rilmenidine stimulates both Ca2+ release from intracellular stores and Ca2+ influx by a mechanism independent of alpha2-adrenergic receptors. In vivo, rilmenidine may enhance uptake of Ca2+ from the extracellular fluid by astrocytes, a process that may contribute to the neuroprotective effects of this agent.
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PMID:Rilmenidine elevates cytosolic free calcium concentration in suspended cerebral astrocytes. 975 Nov 74

Cerebral ischemia leads to a massive increase in cytoplasmic calcium activity resulting from an influx of calcium ions into cells and a release of calcium from mitochondria and endoplasmic reticulum (ER). It is widely believed that this increase in cytoplasmic calcium activity plays a major role in ischemic cell injury in neurons. Recently, this concept was modified, taking into account that disturbances occurring during ischemia are potentially reversible: it then was proposed that after reversible ischemia, calcium ions are taken up by mitochondria, leading to disturbances of oxidative phosphorylation, formation of free radicals, and deterioration of mitochondrial functions. The current review focuses on the possible role of disturbances of ER calcium homeostasis in the pathologic process culminating in ischemic cell injury. The ER is a subcellular compartment that fulfills important functions such as the folding and processing of proteins, all of which are strictly calcium dependent. ER calcium activity is therefore relatively high, lying in the lower millimolar range (i.e., close to that of the extracellular space). Depletion of ER calcium stores is a severe form of stress to which cells react with a highly conserved stress response, the most important changes being a suppression of global protein synthesis and activation of stress gene expression. The response of cells to disturbances of ER calcium homeostasis is almost identical to their response to transient ischemia, implying common underlying mechanisms. Many observations from experimental studies indicate that disturbances of ER calcium homeostasis are involved in the pathologic process leading to ischemic cell injury. Evidence also has been presented that depletion of ER calcium stores alone is sufficient to activate the process of programmed cell death. Furthermore, it has been shown that activation of the ER-resident stress response system by a sublethal form of stress affords tolerance to other, potentially lethal insults. Also, disturbances of ER function have been implicated in the development of degenerative disorders such as prion disease and Alzheimer's disease. Thus, disturbances of the functioning of the ER may be a common denominator of neuronal cell injury in a wide variety of acute and chronic pathologic states of the brain. Finally, there is evidence that ER calcium homeostasis plays a key role in maintaining cells in their physiologic state, since depletion of ER calcium stores causes growth arrest and cell death, whereas cells in which the regulatory link between ER calcium homeostasis and protein synthesis has been blocked enter a state of uncontrolled proliferation.
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PMID:Disturbances of the functioning of endoplasmic reticulum: a key mechanism underlying neuronal cell injury? 988 51

The neuroprotective role of the expression of heat shock protein (HSP) and immediate early gene remains unclear. Using immunoelectron microscopy, we examined the ultrastructural integrity of the neurons with expression of c-Fos, c-Jun and HSP70 in gerbils after transient cerebral ischemia and reperfusion. Induction of c-Fos and c-Jun was observed in the CA3 region resistant to ischemia, while HSP70 was expressed not only in the CA3 but also in the vulnerable CAI region. With immunoelectron microscopy, the expression of c-Fos/c-Jun and HSP70 was observed in the neurons which retained neuronal integrity except for mitochondrial swelling and polyribosomal disaggregation. In contrast, the CAI neurons without immunoreaction for HSP70 showed cytoplasmic vacuoles and parallel stacking of rough endoplasmic reticulum, the features associated with the process of delayed neuronal death. These findings suggested that c-Fos and c-Jun were induced selectively in reversibly damaged neurons, whereas HSP70 was up-regulated even in neurons with irreversible damage, but was more preferentially and intensely expressed in neurons with reversible damage.
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PMID:Immunoelectron microscopic study of c-Fos, c-Jun and heat shock protein after transient cerebral ischemia in gerbils. 993 Aug 91

We examined the effect of ischemia on inositol 1,4,5-trisphosphate receptor-induced Ca2+ release by functional and morphological approaches, using the gerbil model after 6-h unilateral occlusion of the common carotid artery. Autoradiographic study revealed that the basal uptake of 45Ca2+ into the endoplasmic reticulum and caffeine-induced 45Ca2+ release from the endoplasmic reticulum were normal in the presence of ATP in each ischemic brain region, whereas inositol 1,4,5-trisphosphate receptor-induced 45Ca2+ release from the endoplasmic reticulum was inhibited only in the CA1 region of the hippocampus on the ischemic side. In moderately ischemic gerbils, electron microscopic study demonstrated aggregation of swollen endoplasmic reticulum in the CA1 region of the hippocampus, so that abundant endoplasmic reticulum assembled in close contact to form endoplasmic reticulum cisternal stacks. In severely ischemic gerbils, immunohistochemical analysis of the hippocampus showed loss of type 1 inositol 1,4,5-trisphosphate receptor protein with preservation of immunoreactivity for type 2 and 3 inositol 1,4,5-trisphosphate receptor proteins, which was confirmed by western blot analysis. Such selective inhibition of inositol 1,4,5-trisphosphate receptor-induced Ca2+ release and the loss of type 1 inositol 1,4,5-trisphosphate receptor in the CA1 region of the hippocampus in cerebral ischemia may be associated with its region-specific vulnerability to ischemia.
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PMID:Selective inhibition of inositol 1,4,5-triphosphate-induced Ca2+ release in the CA1 region of the hippocampus in the ischemic gerbil. 1047 64

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of brain injury after focal cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose deprivation and chemical hypoxia compared to their wild-type counterparts. Calcium imaging studies demonstrated enhanced elevation of intracellular calcium levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant mice. Agents that block calcium release from IP(3)- and ryanodine-sensitive stores (xestospongin and dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.
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PMID:Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis. 1066 26

The ability of full and partial benzodiazepine receptor agonists to prevent DNA fragmentation and neuronal death after transient cerebral ischemia was investigated in the Mongolian gerbil. Diazepam (10mg/kg, i.p.) or the partial agonist imidazenil (3mg/kg, i.p.) was administered 30 and 90min after transient forebrain ischemia produced by occlusion of the carotid arteries for 5min. Treatment with diazepam completely protected CA1b hippocampal pyramidal neurons in 94% of the animals and partially protected pyramidal neurons in 6% of the animals, as assessed with a standard Nissl stain three and four days after ischemia. DNA fragmentation was examined by the terminal dUTP nick-end labeling (TUNEL) reaction. Prior to cell death, there were no TUNEL-positive neurons in area CA1b. By three days after ischemia, when neuronal degeneration was nearly complete, 14 out of 16 gerbils exhibited a positive TUNEL reaction throughout area CA1b stratum pyramidale. In 13 out of 14 gerbils treated with diazepam, no TUNEL-positive neurons were observed in this region. Imidazenil was less effective than diazepam with respect to both neuroprotection and prevention of DNA fragmentation. Three days after ischemia, six out of eight gerbils treated with imidazenil showed partial to complete neuroprotection. Imidazenil completely prevented DNA fragmentation in only one of the animals; varying degrees of TUNEL reaction persisted in the remainder. To determine whether the neurons protected by diazepam had a normal ultrastructure, gerbils were killed two to 30 days after ischemia and the hippocampal neurons in area CA1b were examined by electron microscopy. Within the first 48h after ischemia, early cytoplasmic changes of varying degrees (e.g., vacuolation, rough endoplasmic reticulum stacking, swollen mitochondria) and electron-dense dendrites were observed in gerbils not treated with diazepam. Degeneration was nearly complete by three days after ischemia. In contrast, pyramidal neuron ultrastructure appeared normal in gerbils that exhibited complete area CA1b neuroprotection (defined at the light microscope level) by diazepam when studied two, seven or 30 days after ischemia. In gerbils with partial protection of area CA1b, most of the remaining neurons exhibited varying degrees of necrosis when studied 30 days after ischemia. No apoptotic bodies were observed. We conclude that: (i) diazepam can fully protect CA1 pyramidal cells from the toxic effects of transient cerebral ischemia; (ii) when diazepam affords only partial neuroprotection, the residual CA1 pyramidal cells exhibit ultrastructural abnormalities consistent with necrotic damage; and (iii) diazepam is a more efficacious neuroprotectant than the partial benzodiazepine receptor agonist, imidazenil.
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PMID:Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study. 1086 41

The endoplasmic reticulum (ER) is a subcellular compartment playing a pivotal role in the control of vital calcium-related cell functions, including calcium storage and signalling. In addition, newly synthesized membrane and secretory proteins are folded and processed in the ER, reactions which are strictly calcium dependent. The ER calcium activity is therefore high, being several orders of magnitude above that of the cytoplasm. Depletion of ER calcium stores causes an accumulation of unfolded proteins in the ER lumen, a pathological situation which induces the activation of two highly conserved stress responses, the ER overload response (EOR) and the unfolded protein response (UPR). EOR triggers activation of the transcription factor NF kappa B, which, in turn, activates the expression of target genes. UPR triggers two downstream processes: it activates the expression of genes coding for ER-resident stress proteins, and it causes a suppression of the initiation of protein synthesis. A similar stress response is activated in pathological states of the brain including cerebral ischaemia, implying common underlying mechanisms. Depending on the extent and duration of the disturbance, an isolated impairment of ER function is sufficient to induce cell injury. In this review, evidence is presented that ER function is indeed disturbed in various diseases of the brain, including acute pathological states (e.g. cerebral ischaemia) and degenerative diseases (e.g. Alzheimer's disease). A body of evidence suggests that disturbances of ER function could be a global pathomechanism underlying neuronal cell injury in various acute and chronic disorders of the central nervous system. If that is true, restoration of ER function or attenuation of secondary disturbances induced by ER dysfunction could present a highly promising new avenue for pharmacological intervention to minimize neuronal cell injury in different pathological states of the brain.
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PMID:Dependence of vital cell function on endoplasmic reticulum calcium levels: implications for the mechanisms underlying neuronal cell injury in different pathological states. 1113 51

It is widely believed that calcium plays a primary role in the development of neuronal cell injury in different pathological states of the brain. Disturbances of calcium homeostasis may be induced in three different subcellular compartments, the cytoplasm, mitochondria or the endoplasmic reticulum (ER). The traditional calcium hypothesis holds that neuronal cell injury is induced by a marked increase in cytoplasmic calcium activity during stress (e.g., cerebral ischemia). Recently, this hypothesis has been modified, taking into account that under different experimental conditions the extent of cell injury does not correlate closely with calcium load or total calcium influx into the cell, and that neuronal cell injury has been found to be associated with both increases and decreases of cytoplasmic calcium activity. The mitochondrial calcium hypothesis is based on the observation that after a severe form of stress there is a massive influx of calcium ions into mitochondria, which may lead to production of free radicals, opening of the mitochondrial permeability transition (MPT) pore and disturbances of energy metabolism. However, it has still to be established whether drugs such as cyclosporin A are neuroprotective through their effect on MPT or through the blocking of processes upstream of MPT. The ER calcium hypothesis arose from the observation that ER calcium stores are depleted after severe forms of stress, and that the response of cells to disturbances of ER calcium homeostasis (activation of the expression of genes coding for ER resident stress proteins and suppression of the initiation of protein synthesis) resembles their response to a severe form of stress (e.g., transient ischemia) implying common underlying mechanisms. Elucidating the exact mechanisms of calcium toxicity and identifying the subcellular compartment playing the most important role in this pathological process will help to evaluate strategies for specific therapeutic intervention.
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PMID:Role of calcium in neuronal cell injury: which subcellular compartment is involved? 1113 96


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