Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathological isoform of the prion protein (PrP(Sc)) has been identified to mediate transmissible spongiform encephalopathies like Creutzfeldt-Jakob disease (CJD). In contrast, the physiological function of the normal cellular prion protein (PrP(c)) is not yet understood. Recent findings suggest that PrP(c) may have neuroprotective properties and that its absence increases susceptibility to oxidative stress and neuronal injury. To determine whether PrP(c) is part of the cellular response to neuronal injury in vivo, we investigated PrP(c) regulation after severe and mild focal ischemic brain injury in mice using the thread occlusion stroke model. Western Blot and ELISA analysis showed a significant upregulation of PrP(c) in the ischemic hemisphere at 4 and 8h after onset of permanent focal ischemia, which was no longer detectable at 24h after lesion induction when compared to control animals. In contrast, transient focal ischemia (60 min) did only lead to slightly but not significantly elevated PrP(c) levels in the ischemic hemisphere when compared to controls. These results demonstrate that cerebral PrP(c) is upregulated early in response to focal cerebral ischemia. The extent of upregulation, however, seems to depend on the severity of ischemia and may therefore reflect the extent of ischemia induced neuronal damage. Given the known neuroprotective effects of PrP(c) in vitro, ischemia-induced upregulation of cerebral PrP(c) supports the hypothesis that, as part of an early adaptive cellular response to ischemic brain injury, PrP(c) may be involved in the regulation of ischemia-induced neuronal cell death in vivo.
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PMID:Upregulation of cellular prion protein (PrPc) after focal cerebral ischemia and influence of lesion severity. 1553 Nov 6

Pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and peptide histidine-isoleucine (PHI) belong to a structurally related family of polypeptides present in many regions of the central and peripheral nervous system. The neuroprotective potential of PACAP, VIP, and PHI has become a matter of intensive investigations in many animal models. In vitro studies revealed that PACAP protects neurons against apoptosis occurring naturally during CNS development and apoptosis induced by a series of neurotoxins, such as ethanol, hydrogen peroxide (H2O2), prion protein, beta-amyloid, HIV envelope glycoprotein (gp120), potassium ion deficit, and high glutamate concentrations. Similarly, in vivo investigations conducted in models of ischemia and Parkinson's disease confirmed the neuroprotective properties of PACAP. It was revealed that the anti-apoptotic action of PACAP can be directly associated with the activation of signal transduction pathways preventing apoptosis in neurons or involve glial cells capable of releasing other neuroprotective factors affecting neurons. In contrast to PACAP, the neuroprotective action of VIP depends mainly on stimulation of astrocytes to produce and secrete factors of extremely high neuroprotective potential, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP). It was shown that ADNF and ADNP, as well as their shortened derivatives ADNF-9 and NAP, prevent neurons from electrical blockade, excitotoxicity, apoE deficiency, glucose deficit, ischemia, toxic action of ethanol, beta-amyloid, and gp120. The neuroprotective potential of PHI has not been as thoroughly investigated yet, but recent data have confirmed that this peptide can also function as a neuroprotectant. It is thought that PACAP, VIP, and possibly PHI may serve as a goal of modern therapeutic strategies in various neurodegenerative disorders.
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PMID:[Neuroprotective role of PACAP, VIP, and PHI in the central nervous system]. 1557 49

Pituitary adenylate cyclase activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI), are structurally related endogenous peptides widely expressed in the central and peripheral nervous system and showing rich profile of biological activities. They act as neurotransmitters, neuromodulators and neurotrophic factors. Recently, their neuroprotective potential has been revealed in numerous in vitro and in vivo models. Thus, PACAP and VIP protected the cells from neurotoxic effects of ethanol, hydrogen peroxide (H2O2, beta-amyloid and glycoprotein 120 (gp120). Moreover, PACAP showed neuroprotection against glutamate, human prion protein fragment 106-126 [PrP(106-126)] and C2-ceramide. Both peptides reduced brain damage after ischemia and ameliorated neurological deficits in a model of Parkinson's disease. Neuroprotective potential of PHI has not been thoroughly investigated yet, but several results obtained in the last years do not exclude it. The mechanism underlying neuroprotective properties of PACAP seems to involve activation of adenylyl cyclase (AC) --> cyclic adenosine 3',5'-mono-phosphate (cAMP) --> protein kinase A (PKA) and mitogen-activated protein (MAP) kinase pathways, and inhibition of caspase-3. PACAP can also, yet indirectly, stimulate astrocytes to release neuroprotective factors, such as regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein 1 (MIP-1) chemokines. Neuroprotective activity of VIP seems to involve an indirect mechanism requiring astrocytes. VIP-stimulated astrocytes secrete neuroprotective proteins, including activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP), as well as a number of cytokines. However, in the activated microglia, VIP and PACAP are capable of inhibiting the production of inflammatory mediators which can lead to neurodegenerative processes within the brain. In conclusion, studies carried out on the central nervous system have shown that PACAP, VIP, and likely PHI, are endowed with a neuroprotective potential, which renders them (or their derivatives) promising therapeutic agents in several psychoneurological disorders linked to neurodegeneration.
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PMID:Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. 1598 13

This study was designed to examine the function of cellular prion protein and prion protein-like protein/Doppel, in transient ischemia-related neuronal death in the hippocampus. Two different lines of mice devoid of cellular prion protein, Zrch I Prnp(0/0) and Ngsk Prnp(0/0), were used. The former lacks cellular prion protein whereas the latter ectopically expresses prion protein-like protein/Doppel in the brain in the absence of cellular prion protein. Mice were subjected to 10 min-occlusion of the bilateral common carotid arteries with recovery for 14 days. Less than 10% of the pyramidal neurons in the CA1 subfield were degenerated in male and female wild-type mice. In contrast, more than half of the neurons were lost in male Zrch I Prnp(0/0) and Ngsk Prnp(0/0) mice. Such severe neuronal loss was also observed in female Ngsk Prnp(0/0) mice. However, female Zrch I Prnp(0/0) mice showed mild neuronal loss similar to wild-type mice. Flunarizine, a T- and L-type Ca(2+)-channel antagonist, significantly reduced the neuronal loss in female but not in male Ngsk Prnp(0/0) mice. These results indicate that loss of cellular prion protein renders hippocampal neurons susceptible to ischemic insult specifically in male but not female mice and the ectopic expression of prion protein-like protein/Doppel aggravates the ischemic neuronal death in female prion protein-null mice probably via overloading of Ca(2+)-dependent signaling.
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PMID:Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein. 1619 94

Cellular prion protein (PrP(C)), a copper-binding glycosyl-phosphatidylinositol (GPI)-anchored membrane protein that is expressed predominantly in neurons can be induced in ischemia/hypoxic brain tissues. It was also found to be overexpressed and conferred multidrug resistance, promoting cancer metastasis and inhibiting apoptosis in gastric cancer in our lab. In solid tumors, hypoxia can promote malignant progression and confer resistance to chemotherapy by altering gene expression. In present study, we investigated the molecular mechanisms and signaling pathway involved in the induction of the PrP(C) gene by hypoxia in cancer cell lines. PrP(C) was detected to be upregulated in several cancer cell lines at both mRNA and protein level, and then found to be induced by hypoxia in a time-dependent manner. After hypoxia treatment, gastric cancer MKN28 cells transfected with luciferase reporter constructs of the human PrP(C) promoter, which contained HSE, expressed higher luciferase activities (4.3-fold) than those cells transfected with the constructs containing no HSE. In addition, the upregulation of PrP(C) was reduced by MERK/ERK inhibitor (PD98059). siRNA knockdown of PrP(C) could make the cells more sensitive to hypoxia induced drug sensitivity. In conclusion, from these findings, we can propose that some transcriptional factors phosphorylated by ERK1/2, could in turn interact with HSE in the promoter of PrP(C) resulting in upregulation of PrP(C) in gastric cancer cell line MKN28 during hypoxia. Downregulation of PrP(C) makes gastric cancer cells more sensitive to hypoxia induced drug sensitivity. However, other mechanisms might also be responsible for hypoxia induced overexpression of PrP(C) in gastric cancer.
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PMID:Hypoxia induced overexpression of PrP(C) in gastric cancer cell lines. 1738 71

Structural alterations of the cellular prion protein (PrP(C)) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrP(C )remains an enigma. Cell culture experiments have indicated that PrP(C) and in particular its N-terminal octarepeat region together with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways have a fundamental involvement in neuroprotection and oxidative stress reactions. We used wild-type mice, PrP knockout (Prnp(-/-)) animals and transgenic mice that lack the octarepeat region (C4/-) and subjected them to controlled ischemia. We identified an increased cleavage and synthesis of PrP(C) in ischemic brain areas of wild-type mice compared with sham controls. The infarct size in Prnp(-/-) animals was increased threefold when compared with wild-type mice. The infarct size in C4/- animals was identical to Prnp(-/-) mice, that is, around three times larger than in wild-type mice. We showed that the PrP in C4/- mice does not functionally rescue the Prnp(-/-) phenotype; furthermore it is unable to undergo beta cleavage, although an increased amount of C1 fragments was found in ischemic brain areas compared with sham controls. We demonstrated that the N-terminal octarepeat region has a lead function in PrP(C) physiology and neuroprotection against oxidative stress in vivo.
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PMID:The role of the octarepeat region in neuroprotective function of the cellular prion protein. 1738 48

Knowledge of the physiological function of cellular prion protein has been acquired from prion diseases such as Creutzfeldt-Jakob disease, as well as PRNP knock out and transgenic mice. Recent progress in neurobiology has further delineated the neuroprotective role played by cellular prion protein. In this paper, we review the role of cellular prion protein in cell survival including its antiapoptotic effect on Bax-mediated cell death and its responses to various environmental stresses including oxidative stress, and ischemia. Finally, we discuss the significance of cellular prion protein in different neurodegenerative diseases and the possible development of future therapies.
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PMID:New molecular insights into cellular survival and stress responses: neuroprotective role of cellular prion protein (PrPC). 1791 12

Humanin (HN) is an anti-apoptotic peptide that suppresses neuronal cell death induced by Alzheimer's disease, prion protein fragments, and serum deprivation. Recently, we demonstrated that Gly14-HN (HNG), a variant of HN in which the 14th amino acid serine is replaced with glycine, can decrease apoptotic neuronal death and reduce infarct volume in a focal cerebral ischemia/reperfusion mouse model. In this study, we postulate that the mechanism of HNG's neuroprotective effect is mediated by the PI3K/Akt pathway. Oxygen-glucose deprivation (OGD) was performed in cultured mouse primary cortical neurons for 60 min. The effect of HNG and PI3K/Akt inhibitors on OGD-induced cell death was examined at 24 h after reperfusion. HNG increased cell viability after OGD in primary cortical neurons, whereas the PI3K/Akt inhibitors wortmannin and Akti-1/2 attenuated the protective effect of HNG. HNG rapidly increased Akt phosphorylation, an effect that was inhibited by wortmannin and Akti-1/2. Mouse brains were injected intraventricularly with HNG before being subjected to middle cerebral artery occlusion (MCAO). HNG treatment significantly elevated p-Akt levels after cerebral I/R injury and decreased infarct volume. The protective effect of HNG on infarct size was attenuated by wortmannin and Akti-1/2. Taken as a whole, these results suggest that PI3K/Akt activation mediates HNG's protective effect against hypoxia/ischemia reperfusion injury.
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PMID:Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. 1859 Jul 9

Murine olfactory ensheathing cells (OECs) promote central nervous system axonal regeneration in models of spinal cord injury. We investigated whether OECs could induce a neuroplastic effect to improve the neurological dysfunction caused by hypoxic/ischemic stress. In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell-derived factor-1alpha (SDF-1alpha). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized with specific neural and vascular markers, indicating stem cell fusion. Both hOECs/ONFs and endogenous homing stem cells enhanced neuroplasticity in the rat and mouse ischemic brain. Upregulation of SDF-1alpha and CXCR4 in hOECs/ONFs promoted neurite outgrowth of cocultured primary cortical neurons under oxygen glucose deprivation conditions and in stroke animals through upregulation of cellular prion protein (PrP C) expression. Therefore, the upregulation of SDF-1alpha and the enhancement of CXCR4 and PrP C interaction induced by hOEC/ONF implantation mediated neuroplastic signals in response to hypoxia and ischemia.
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PMID:Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. 1859 86

Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to brain lesions in experimental models of ischemia, tumors, and neurodegenerative diseases and to ameliorate functional deficits. In this study, we attempted to evaluate the therapeutic potential of MSCs for treating prion diseases. Immortalized human MSCs (hMSCs) that express the LacZ gene were transplanted into the unilateral hippocampi or thalami of mice, and their distributions were monitored by the expression of beta-galactosidase. In mice infected with prions, hMSCs transplanted at 120 days postinoculation (dpi) were detected on the contralateral side at 2 days after transplantation and existed there even at 3 weeks after transplantation. In contrast, few hMSCs were detected on the contralateral side for mock-infected mice. Interestingly, the migration of hMSCs appeared to correlate with the severity of neuropathological lesions, including disease-specific prion protein deposition. The hMSCs also migrated to a prion-specific lesion in the brain, even when intravenously injected. Although the effects were modest, intrahippocampal and intravenous transplantation of hMSCs prolonged the survival of mice infected with prions. A subpopulation of hMSCs in the brains of prion-infected mice produced various trophic factors and differentiated into cells of neuronal and glial lineages. These results suggest that MSCs have promise as a cellular vehicle for the delivery of therapeutic genes to brain lesions associated with prion diseases and, furthermore, that they may help to regenerate neuronal tissues damaged by prion propagation.
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PMID:Effect of transplantation of bone marrow-derived mesenchymal stem cells on mice infected with prions. 1929 2


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