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)

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

Disturbances in neuronal calcium homeostasis have been implicated in a variety of neuropathological conditions, including cerebral ischemia, hypoglycemia, and epilepsy, and possibly constitute part of the cell death process associated with chronic neurodegenerative disorders. We investigated if endoplasmic reticulum (ER) calcium stores participate in neuronal death triggered by moderate glycolysis inhibition induced by iodoacetate, an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, in cultured hippocampal neurons. Results show that exposure to iodoacetate leads to a slow partial decrease in cell survival, which is significantly prevented in the absence of Ca(2+) or in the presence of the calcium chelator BAPTA-AM. Treatment with caffeine and a low (1 microM) concentration of ryanodine, which activates the ryanodine receptor (RyR), exacerbates neuronal death, whereas dantrolene and 25 microM ryanodine, which antagonizes RyR, prevents damage. Xestospongin C (XeC), an antagonist of the inositol-3-phosphate (IP(3)) receptor (IP(3)R) also prevents neuronal damage. Inhibitors of the ER calcium ATPase (sarcoendoplasmic reticulum Ca(2+) ATPase; SERCA) have no effect. The decrease in ATP levels induced by iodoacetate is potentiated by caffeine and prevented by dantrolene. Although only a slight increase in glutamate extracellular levels is observed 3.5 hr after iodoacetate exposure, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, MK-801, efficiently prevents neuronal damage. Taken together, the data suggest that neuronal death induced during moderate glycolysis inhibition involves calcium influx through NMDA receptors and calcium release from intracellular ER stores. These results might be relevant to the understanding the mechanisms involved in neuronal damage related to aging and chronic neurodegenerative diseases, which have been associated with decreased glucose metabolism.
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PMID:Disruption of endoplasmic reticulum calcium stores is involved in neuronal death induced by glycolysis inhibition in cultured hippocampal neurons. 1617 70

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

Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease.
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PMID:Neuroserpin: a serpin to think about. 1646 51

After ischemia, endoplasmic reticulum (ER) stress pathways are activated that include unfolded protein response (UPR) and protein synthesis inhibition (PSI). Both of these mechanisms aim to restore ER functioning mainly by inhibition of translation and increased processing of excess proteins in ER. We were interested in the role of these pathways during spontaneous recovery after transient middle cerebral artery occlusion (MCAO) in rats. The spontaneous recovery of rats was assessed with a limb-placing test. The expression of ER-stress-related genes (IRE1, ATF6, GRP78, eif2alpha, ATF4, PERK) was studied by using in situ hybridization in different brain areas on post-operative days 2, 7, 14 and 28. Elevated signals were detected in striatum contralateral to the lesion on days 2 (PERK and IRE1) and 14 post-ischemia (IRE1). Gene expression was elevated on day 7 in the striatum ipsilateral to the lesion (ATF6 and GRP78) and on day 14 (GRP78) post-ischemia. Furthermore, elevated levels of GRP78 were detected on day 14 after ischemia in the ipsilateral sensorimotor cortex. These results suggest that altered gene expression related to unfolded protein response may be more long lasting than expected following focal cerebral ischemia. In addition, these results show that the response to ER stress differs ipsi- and contralaterally after MCAO in rats. Since these differences are detected in both hemispheres only in areas adjacent to the lesion, UPR may contribute to spontaneous recovery after MCAO in rats.
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PMID:Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke. 1668 12

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 indicate the existence of autophagy in cerebral ischemia, but the functions of autophagy in this setting remain unclear. Here we discuss the role of autophagy in cerebral ischemia based on our own publication and the literature on this subject. We propose that oxidative and endoplasmic reticulum (ER) stresses n cerebral ischemia-hypoxia are potent stimuli of autophagy in neurons. We also reviewed evidence suggesting autophagosomes may have a shorter half-life in neurons and that a fraction of LC3 protein is degraded within autolysosomes, leading to a smaller detectable amount of LC3-II in the brain while there are clear indications of on-going autophagy. Finally, we suggest autophagy is an important modifier of cell death and survival, interacting with necrosis and apoptosis in determining the outcomes and final morphology of deceased neurons.
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PMID:The roles of autophagy in cerebral ischemia. 1687 57

The endoplasmic reticulum (ER) is important for maintaining the quality of cellular proteins. Various stimuli can disrupt ER homeostasis and cause the accumulation of unfolded or misfolded proteins, i.e., a state of ER stress. Recently, ER stress has been reported to play an important role in the pathogenesis of neurological disorders such as cerebral ischemia and neurodegenerative diseases, but its involvement in the spinal cord diseases has not been fully discussed. We conducted this study using tunicamycin (Tm) as an ER stress inducer for rat spinal cord in organotypic slice culture, a system that we have recently established. Tm was shown to induce ER stress by increased expression of GRP78. The viability rate of spinal cord neurons decreased in a dose-dependent manner with Tm treatment, and dorsal horn interneurons were more vulnerable to Tm-induced neurotoxicity. A p53 inhibitor significantly increased the viability of dorsal horn interneurons, and immunofluorescence studies showed nuclear accumulation of p53 in the dorsal horns of Tm-treated spinal cord slices. These findings suggest that p53 plays an important role in the killing of dorsal horn interneurons by Tm. In contrast, motor neurons were not protected by the p53 inhibitor, suggesting that the role of p53 may vary between different cell types. This difference might be a clue to the mechanism of the stress-response pathway and might also contribute to the potential application of p53 inhibitors for the treatment of spinal cord diseases, including amyotrophic lateral sclerosis.
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PMID:Role of p53 in neurotoxicity induced by the endoplasmic reticulum stress agent tunicamycin in organotypic slice cultures of rat spinal cord. 1713 18

Stress is the imbalance of homeostasis, which can be sensed even at the subcellular level. The stress-sensing capability of various organelles including the endoplasmic reticulum (ER) has been described. It has become evident that acute or prolonged ER stress plays an important role in many human diseases; especially those involving organs/tissues specialized in protein secretion. This article summarizes the emerging role of ER stress in diverse human pathophysiological conditions such as carcinogenesis and tumor progression, cerebral ischemia, plasma cell maturation and apoptosis, obesity, insulin resistance, and type 2 diabetes. Certain components of the ER stress response machinery are identified as biomarkers of the diseases or as possible targets for therapeutic intervention.
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PMID:Endoplasmic reticulum stress. 1748 6

Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (<48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (approximately 650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.
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PMID:Cerebral ischemia causes dysregulation of synaptic adhesion in mouse synaptosomes. 1751 75


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