Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative damage to the endoplasmic reticulum (ER) could be involved in ischemic neuronal cell death because this organelle is susceptible to reactive oxygen species. Using wild-type mice and copper/zinc-superoxide dismutase (SOD1) transgenic mice, we induced focal cerebral ischemia and compared neuronal degeneration and ER stress, that is, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK). We found that neurons with severe and prolonged phosphorylation of eIF2alpha and PERK underwent later degeneration, and that this was partially prevented by SOD1 overexpression. Signals for superoxide production and phospho-PERK were colocalized, which further indicates a pivotal role for superoxide in ER damage. We investigated the molecular mechanisms of oxidative ER stress and found that detachment of glucose-regulated protein 78 from PERK was the key step. We conclude that ER damage is involved in oxidative neuronal injury in the brain after ischemia/reperfusion.
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PMID:Oxidative injury to the endoplasmic reticulum in mouse brains after transient focal ischemia. 1500 93

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.
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PMID:S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. 1672 68

Recent studies have suggested that neuronal apoptosis in cerebral ischemia could arise from dysfunction of endoplasmic reticulum (ER) and mitochondria. B-cell lymphoma/leukemia-2 gene (Bcl-2) has been described as an inhibitor both in programmed cell death (PCD) and ER dysfunction during apoptosis, and the Bcl-2 family play a key role in regulating the PCD, both locally at the ER and from a distance at the mitochondrial membrane. However, its signal pathways and concrete mechanisms in endoplasmic reticulum-initiated apoptosis remain incompletely understood. We therefore investigate whether ischemia/reperfusion (I/R) causes neuronal apoptosis in part via cross-talk between ER and mitochondria or not, and how the overexpression of Bcl-2 prevents this form of cell death. Here we show that analogous I/R-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. The participation of the mitochondrial pathway was demonstrated by the release of cytochrome C (cyt C) from mitochondrial into cytoplasmic fractions and caspase-9 cleavage. The involvement of ER stress was further supported by the observable increase of glucose-regulated protein 78(GRP78)/BiP expression and caspase-12 activity. Furthermore, prior to these changes, swelling of the ER lumen and dissociation of ribosomes from rough ER were detected by electron microscopy. Bcl-2 overexpression inhibits the release of cyt C and the activation of caspase-9/-8/-3 but not caspase-12 based on the results of Western blot. These suggest that cross-talk between ER and mitochondria participate in neuronal damage after ischemia/reperfusion. Bcl-2 overexpression could suppress I/R-induced neuronal apoptosis via influencing mitochondrial integrity.
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PMID:The protection of Bcl-2 overexpression on rat cortical neuronal injury caused by analogous ischemia/reperfusion in vitro. 1872 55

Mild NMDA receptor activation is correlated with neuroprotection in models of cerebral ischemia. Neuroprotection with NMDA manifests as a form of ischemic tolerance and involves the induction of cellular stress systems sensitive to disturbances in cellular calcium homeostasis. Unilateral micro-injection of 10, 160 and 320 microM NMDA into the prefrontal cortex of a rat 30 min prior to permanent occlusion of the middle cerebral artery (MCAO) significantly reduced the area of infarct observed after 4 h of ischemia. The highest dose of NMDA (320 microM) prevented the propagation of ischemic damage through a direct toxicity on neuronal tissue adjacent to the injection site as demonstrated in thionin-stained sections. As a result, the degree of ischemia-induced damage was similar to that measured in rats pretreated with the low dose of NMDA (10 microM). Expression of heat shock protein (HSP) 70 and glucose-regulated protein (GRP) 94 in cortical samples taken from the region of infarct following MCAO was significantly reduced in rats pretreated with 10 microM NMDA compared to saline-injected control rats and rats pretreated with higher doses of NMDA. Furthermore, 10 microM NMDA did not appear to influence expression of m-calpain or GRP78, however, higher doses of NMDA did significantly induce expression of both proteins as assessed by Western blotting. In summary, our data demonstrate an in vivo rodent model of ischemic tolerance in which 30 min of neuronal preconditioning with 10 microM NMDA confers protection against a 4 h period of MCAO-induced ischemia. This effect may involve modulation of cellular stress signals, in particular HSP70 and GRP94.
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PMID:Ischemic tolerance following low dose NMDA involves modulation of cellular stress proteins. 1899 20

Apolipoprotein E-deficient (apoE(-/-)) mice have been shown to have increased vulnerability to neuronal damage induced by cerebral ischemia; however, the mechanism of this increased vulnerability remains unclear. In order to define the role of the apoE protein against ischemia-induced ER stress and cell death, experiments were performed to compare ER stress-associated chaperones and signal proteins in the hippocampus of apoE(-/-) mice to those of WT mice after being subjected to forebrain ischemia and reperfusion. Although neuronal loss in area CA1-CA3 of the hippocampus was observed 3 days after ischemia in both types of mice, the damage in apoE(-/-) mice was more severe. In apoE(-/-) mice, a more extensive increase in 78-kDa glucose-regulated protein (GRP78) was observed after the insult, whereas the level of GRP94 was not changed. The expression of both C/EBP homologous protein (CHOP) and caspase-12 was increased in the hippocampus in both WT and apoE(-/-) mice after ischemia. The increased levels of CHOP in apoE(-/-) mice were significantly higher than those in WT mice, whereas the levels of caspase-12 in the two were comparable. Furthermore, whereas the levels of c-Jun N-terminal kinase (JNK), p-JNK1 and p-JNK2 in WT mice were unchanged after ischemia, they were significantly increased in apoE(-/-) mice 24h and 48h after ischemia. These results suggest that increased vulnerability of the hippocampus to forebrain ischemia and reperfusion in apoE(-/-) mice is at least partly attributable to perturbed induction of an ER chaperone, GRP 94, and enhancement of the CHOP- and JNK-dependent apoptotic pathway in the hippocampus.
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PMID:Apolipoprotein E-deficient mice are more vulnerable to ER stress after transient forebrain ischemia. 1942 81

The endoplasmic reticulum(ER) stress plays a vital role in mediating ischemic neuronal cell death. However, very little is known about the role of ER stress in mediating pathophysiological reactions to acute brain injuries. An attempt was therefore made to assess the role of cerebral ischemia/reperfusion (I/R) induced ER stress and its modulation on outcome of ischemic insult. Focal cerebral ischemia was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h followed by varying time points of reperfusion. The brain loci specific and time-dependent alterations were seen in the expression pattern of molecular markers, i.e., heat-shock protein 70 (HSP70) for cytoplasmic dysfunction, glucose-regulated protein 78 (GRP78), Caspase-12, C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), activating transcription factor 4 (ATF-4), and Processed X-box protein 1 (xbp1) mRNA for ER dysfunction. Further, histological examinations indicated pronounced brain damage, massive neuronal loss, and DNA fragmentation predominantly in the striatum and cortex. The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain regions clearly indicate the critical involvement of ER-mediated cell death/survival mechanisms and also collectively demonstrated the activation of unfolded protein response (UPR). Moreover, Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha), leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as key therapeutic target for neuroprotection.
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PMID:Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats. 1976 36

In animal models, endoplasmic reticulum (ER) stress and apoptosis take place around cerebral infarction areas during ischemia, which presumably protect tissues from necroses-induced injury as well as promote cells toward death. We examined whether these pathological changes, especially temporal occurrence, were present in patients who suffered from cerebral ischemia. The studies by immunohistochemistry show that ER chaperone glucose-regulated protein (GRP78) and caspase-9 elevate around infarction areas. The experiments by terminal deoxynucleotidy transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick-end labeling (TUNEL) illustrate that TUNEL-positive cells are higher around infarction tissues than controls. Moreover, GRP78, caspase-9 and TUNEL cells emerge one after another during ischemia. In conclusion, ER stress, apoptosis initiation and DNA fragment develop sequentially in ischemic human brain. ER stress during excessive ischemia stimulates apoptotic cell death beyond activating a defense for nerve cells being away from injury.
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PMID:Ischemia induces endoplasmic reticulum stress and cell apoptosis in human brain. 2034 37

Transient forebrain ischemia has been shown to cause neuronal injury in the CA1 area of the hippocampus in mice. In addition to neuronal injury, astrocytes in area CA1 undergo apoptosis under ischemic conditions. Although failure of impaired astrocytes to take up glutamate is thought to contribute to the pathogenesis of cerebral ischemia, the molecular mechanism underlying this phenomenon remains unexplored. In the present study, we investigated neuronal and astroglial responses to endoplasmic reticulum (ER) stress, which is an important sequela of transient forebrain ischemia in the hippocampus of mice. Cellular injury was observed in area CA1 of the hippocampus 72h after reperfusion, and ssDNA positivity was detectable in some glial cells as well as neurons in this area. An increase of 78-kDa glucose-regulated protein (GRP78), an indicator of ER stress, was detected in pyramidal neurons and astrocytes in this area after the insult. Immunohistochemical analysis showed that caspase-12 was increased in pyramidal neurons and astrocytes located in the extrapyramidal cell layer. Immunoreactivity for C/EBP homologous protein (CHOP) was increased significantly in pyramidal cells but not in astrocytes. These results suggest that astrocytes as well as pyramidal neurons in area CA1 undergo apoptosis through an ER stress-dependent mechanism after ischemia. Unlike the situation in neuronal apoptosis, CHOP does not play a role in the cell death of astrocytes.
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PMID:Characterization of neuronal and astroglial responses to ER stress in the hippocampal CA1 area in mice following transient forebrain ischemia. 2036 24

Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson disease, and cerebral ischemia. In this study, we investigated the effects of apigenin on ER stress-induced apoptosis in murine HT22 hippocampal neuronal cells. Apigenin reduced apoptotic cell death of HT22 cells induced by thapsigargin (TG) and brefeldin A (BFA), two representative ER stress inducers. Consistent with these findings, apigenin blocked TG- and BFA-induced activation of caspase-12 and -3 and cleavage of poly (ADP-ribose) polymerase. Apigenin also reduced the TG- and BFA-induced expression of ER stress-associated proteins, including C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and GRP94, the cleavage of activating transcription factor 6alpha, the phosphorylation of eukaryotic initiation factor 2alpha and inositol-requiring enzyme 1alpha, and the activation of mitogen-activated protein kinases, such as p38, c-Jun NH(2)-terminal kinase, and extracellular-regulated kinase. We also found that antioxidants such as N-acetylcysteine and glutathione blocked TG- and BFA-induced cell death and the expression of CHOP and GRP78. These results suggest that TG- and BFA-induced reactive oxygen species (ROS) accumulation plays an important role in ER stress-induced apoptosis. Apigenin also reduced TG- and BFA-induced ROS accumulation, suggesting that it exerts an antioxidant effect against ER stress inducers. Moreover, apigenin recovered TG- and BFA-induced reduction of the mitochondrial membrane potential in HT22 cells. Taken together, these results suggest that apigenin could protect HT22 neuronal cells against ER stress-induced apoptosis by reducing CHOP induction as well as ROS accumulation and mitochondrial damage.
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PMID:Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. 3110 77

Endoplasmic reticulum (ER) stress has been implicated in the pathology of cerebral ischemia. During prolonged period of stress or when the adaptive response fails, apoptotic cell death ensues. Cerebral ischemic postconditioning (Postcond) has been shown to reduce cerebral ischemia/reperfusion (I/R) injury in both focal and global cerebral ischemia model. However, the mechanism remains to be understood. This study aimed to elucidate whether Postcond attenuates brain I/R damage by suppressing ER stress-induced apoptosis and if the phosphatidylinositol-3kinase/Akt (PI3K/Akt) pathway is involved. A focal cerebral ischemia rat model was used in the study. Rat brain infarct size and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in ischemic penumbra were assessed after reperfusion of the brain. The expressions of C/EBP-homologous protein (CHOP), caspase-12, glucose-regulated protein 78 (GRP78) and the phosphorylation of Akt (Ser473) in ischemic penumbra were measured after reperfusion. Our results showed that Postcond significantly attenuated brain I/R injury, as shown by reduction in infarct size, cell apoptosis, CHOP expression, caspase-12 activation and increase in GRP78 expression. LY294002, a phosphoinositide 3-kinase inhibitor, increased the number of TUNEL-positive cells suppressed by Postcond in penumbra. In addition, LY294002 diminished the effect of Postcond on the activation of CHOP, caspase-12 and GRP78. These results suggest that Postcond protects brain from I/R injury by suppressing ER stress-induced apoptosis and PI3K/Akt pathway is involved.
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PMID:Ischemic postconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PI3K-Akt pathway. 2094 1


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