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)

We have previously reported that dauricine protects brain tissues from focal cerebral ischemia. To corroborate this effect, neurotoxicity due to hypoxia and hypoglycemia was assessed in primary cultures of rat cortical neurons by using a trypan blue exclusion method. To further clarify the mechanism, the intracellular Ca2+ concentration ([Ca2+]i) and mitochondrial membrane potential (Deltapsim) of dissociated rat cortical cells were monitored by fura-2 fluorescence measurements and flow cytometry, respectively. The results showed that 1 and 10 micromol/L dauricine significantly enhanced neuronal survival during 4 h of hypoxia and hypoglycemia. Dauricine inhibited the increase in [Ca2+]i and decrease in Deltapsim induced by 30 min of hypoxia and hypoglycemia. When exploring the pathway, we found that 1 micromol/L dauricine inhibited the [Ca2+]i increase induced by 7.5 nmol/L thapsigargin in either the presence or absence of extracellular Ca2+ and by 1 mmol/L L-glutamate in the presence of extracellular Ca2+. These results suggest that dauricine prevents neuronal loss from ischemia in vitro, which is in accordance with our previous research in vivo. In addition, by inhibiting Ca2+ release from the endoplasmic reticulum and Ca2+ influx from the extracellular space, dauricine suppressed the increase in [Ca2+]i and, subsequently, the decrease in Deltapsim induced by hypoxia and hypoglycemia. This effect may underlie the mechanism of action of dauricine on cerebral ischemia.
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PMID:Neuroprotective effect of dauricine in cortical neuron culture exposed to hypoxia and hypoglycemia: involvement of correcting perturbed calcium homeostasis. 1782 24

The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases and cerebral ischemia. In a screen for compounds that induce the ER-mediated chaperone BiP (immunoglobulin heavy-chain binding protein)/GRP78 (78 kDa glucose-regulated protein), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94 (94 kDa glucose-regulated protein), calreticulin, and C/EBP homologous protein. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements upstream of the BiP gene, through the ATF6 (activating transcription factor 6) pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.
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PMID:A molecular chaperone inducer protects neurons from ER stress. 1804 81

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress that initiates the unfolded protein response (UPR). UPR activates both adaptive and apoptotic pathways, which contribute differently to disease pathogenesis. To further understand the functional mechanisms of UPR, we identified 12 commonly UPR-upregulated genes by expression microarray analysis. Here, we describe characterization of Armet/MANF, one of the 12 genes whose function was not clear. We demonstrated that the Armet/MANF protein was upregulated by various forms of ER stress in several cell lines as well as by cerebral ischemia of rat. Armet/MANF was localized in the ER and Golgi and was also a secreted protein. Silencing Armet/MANF by siRNA oligos in HeLa cells rendered cells more susceptible to ER stress-induced death, but surprisingly increased cell proliferation and reduced cell size. Overexpression of Armet/MANF inhibited cell proliferation and improved cell viability under glucose-free conditions and tunicamycin treatment. Based on its inhibitory properties for both proliferation and cell death we have demonstrated, Armet is, thus, a novel secreted mediator of the adaptive pathway of UPR.
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PMID:Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. 1856 14

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

Cerebral ischemia stimulates Ca2+ influx and thus increases neuronal intracellular free [Ca2+]. Using a rat model of cerebral ischemia without recirculation, we tested whether ischemia enhances the activation by Ca2+ of ryanodine receptor (RyR) channels, a requisite feature of RyR-mediated Ca2+-induced Ca2+ release (CICR). To this aim, we evaluated how single RyR channels from endoplasmic reticulum vesicles, fused into planar lipid bilayers, responded to cytoplasmic [Ca2+] changes. Endoplasmic reticulum vesicles were isolated from the cortex of rat brains incubated without blood flow for 5 min at 37 degrees C (ischemic) or at 4 degrees C (control). Ischemic brains displayed increased oxidative intracellular conditions, as evidenced by a lower ratio (approximately 130:1) of reduced/oxidized glutathione than controls (approximately 200:1). Single RyR channels from ischemic or control brains displayed the same three responses to Ca2+ reported previously, characterized by low, moderate, or high maximal activity. Relative to controls, RyR channels from ischemic brains displayed with increased frequency the high activity response and with lower frequency the low activity response. Both control and ischemic cortical vesicles contained the RyR2 and RyR3 isoforms in a 3:1 proportion, with undetectable amounts of RyR1. Ischemia reduced [3H]ryanodine binding and total RyR protein content by 35%, and increased at least twofold endogenous RyR2 S-nitrosylation and S-glutathionylation without affecting the corresponding RyR3 endogenous levels. In vitro RyR S-glutathionylation but not S-nitrosylation favored the emergence of high activity channels. We propose that ischemia, by enhancing RyR2 S-glutathionylation, allows RyR2 to sustain CICR; the resulting amplification of Ca2+ entry signals may contribute to cortical neuronal death.
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PMID:Ischemia enhances activation by Ca2+ and redox modification of ryanodine receptor channels from rat brain cortex. 1879 78

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of CNS diseases such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia. In the present study, we investigated the effect of pranoprofen, a non-steroidal anti-inflammatory drug (NSAID), on endoplasmic reticulum stress responses in the primary cultured glial cells. Pranoprofen inhibited ER stress-induced glucose regulated protein 78 (GRP78) expression, an ER-localized molecular chaperon. Moreover, pranoprofen inhibited ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) expression, an apoptotic transcription factor. ER stress-induced phosphorylation of alpha-subunit of eukaryotic initiation factor-2 (eIF2alpha) has been reported to be involved in CHOP induction. Interestingly, pranoprofen alone induced eIF2alpha phosphorylation, which was further increased by ER stress. On the other hand, ER stress-induced X-box-binding protein 1 (XBP-1) splicing was inhibited in pranoprofen-treated cells. Thus, the inhibitory effect of pranoprofen on ER stress-related genes (GRP78 and CHOP) would be mediated through the inhibition of XBP-1 splicing. In the present study, pranoprofen has been suggested to affect ER stress. The present results may have important implications for understanding ER stress-related diseases.
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PMID:Effect of pranoprofen on endoplasmic reticulum stress in the primary cultured glial cells. 1911 67

Bcl-2 homology domain 3 (BH3)-only pro-apoptotic proteins may play an important role in upstream cell death signaling pathways underlying ischemic brain injury. Puma is a potent BH3-only protein that can be induced via p53, FoxO3a and endoplasmic reticulum stress pathways and is upregulated by global cerebral ischemia. To more completely define the contribution of Puma to ischemic brain injury we measured the expressional response of Puma to transient focal cerebral ischemia in mice and also compared infarct volumes in puma-deficient versus puma-expressing mice. Real-time quantitative PCR determined puma mRNA levels were significantly increased 8h after 90min middle cerebral artery (MCA) occlusion in the ipsilateral cortex, while expression remained unchanged contralaterally. Puma protein levels were also increased in the ischemic cortex over the same period. However, cortical and striatal infarct volumes were not significantly different between puma-deficient and puma-expressing mice at 24h, and no differences between genotypes were found for post-ischemic neurological deficit scores. These data demonstrate that focal cerebral ischemia is associated with puma induction but suggest that Puma does not contribute significantly to lesion development in the present model.
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PMID:Effects of transient focal cerebral ischemia in mice deficient in puma. 1915 65

Researchers suggest that endoplasmic reticulum (ER) stress cause apoptosis after ischemia. Caspase-12 has been localized to the ER and is a signal for apoptosis. We sought to clarify the role of caspase-12 in the vascular endothelial growth factor (VEGF) induced neuroprotective effect. Transient focal cerebral ischemia was produced by occluding left middle cerebral artery in rabbit. The expressions of caspase-12 and caspase-3 were detected by immunohistochemistry. Neuronal apoptosis was detected by TUNEL staining. We confirmed that the number of apoptotic cells and the expressions of caspase-12 and caspase-3 significantly increased during reperfusion. VEGF inhibited the cell apoptosis and the expressions of caspase-12 and caspase-3. These results suggest that VEGF may protect neurons from apoptosis by inhibiting ER stress pathway.
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PMID:Effect of endoplasmic reticulum stress in VEGF-induced neuroprotection. 1919 Nov 55

Caspase-12 has been localized to endoplasmic reticulum (ER) and showed to involve ER stress-induced apoptosis. In the present work we investigated the temporospatial alterations of caspase-12 immunoreactivity in the penumbra following cerebral ischemia/reperfusion in rabbit. Transient cerebral ischemia was produced by intraluminal occlusion of the middle cerebral artery for 2 h followed by 1 h, 6 h, 1 day, 3 days, 7 days and 14 days of reperfusion. Caspase-12 immunohistochemistry was first increased in the penumbra 1 h after reperfusion, with a peak at day 1 to day 3, and then gradually decreased to basal level at day 14. The number of TUNEL-positive cells and ultrastructural observation of brain sections in the penumbra showed a similar change at the same time points. ER mediated by caspase-12 participated in apoptosis induced by cerebral ischemia/reperfusion injury, which may provide a new area for therapeutic intervention to ameliorate outcomes following cerebral ischemia.
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PMID:Endoplasmic reticulum in the penumbra following middle cerebral artery occlusion in the rabbit. 1938 43

Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as arginine-rich, mutated in early stage of tumors (ARMET), is a secreted protein that reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition that induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MANF after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at 2 days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex.
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PMID:Mesencephalic astrocyte-derived neurotrophic factor reduces ischemic brain injury and promotes behavioral recovery in rats. 1939 76


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