Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary cortical cultures HSVgdnf reduced oxidant-induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex 4 days prior to, or 3 days, after a 60-min unilateral occlusion of the middle cerebral artery. Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed 1 month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein and the apoptotic marker caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS.
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PMID:HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. 1295 87

Previous studies of neuronal degeneration induced by the neurotoxin, kainic acid, employed silver stain techniques that are non-quantitative or ELISA measurement of the non-neuronal protein, glial fibrillary acidic protein. As previous studies employed biomarkers that were either non-quantitative or non-neuronal, the present study employed a new neuronally localized biomaker of neuronal damage, cleaved microtubule-associated protein (MAP)-tau (C-tau). The time course of kainate neurotoxicity was quantitatively determined in several brain regions in the present study employing a C-tau specific ELISA. Differences in ELISA determined regional brain levels of C-tau were compared with the density of somatodendritic C-tau labeling qualitatively determined in immunohistochemical anatomical mapping studies of kainic acid-treated animals. Immunoblot studies revealed that the C-tau antibodies employed in the present study were highly specific for proteolytic cleaved C-tau. Immunolabeling of 45 kD-50 kD C-tau proteins was observed only in brain samples from kainic acid-treated but not vehicle-treated rats. Time course studies revealed that C-tau levels determined by ELISA were maximal 3 days after kainic acid with C-tau levels increasing 26-fold in hippocampus, 16-fold in cortex and four-fold in both striatum and hypothalamus. These statistical differences in maximal C-tau levels observed in the ELISA studies were similar to differences qualitatively observed in C-tau immunohistochemical studies. C-tau immunohistochemistry revealed extensive damage in hippocampal regions CA1 and 3, moderate damage in several cortical regions and mild damage in striatum and hypothalamus. Similar cleavage of rat MAP-tau to C-tau has been reported after neuronal degeneration induced by neurotoxic doses of methamphetamine and neuronal degeneration resulting from bacterial meningitis. In humans, C-tau proteolysis has been demonstrated to be a reliable biomarker of neuronal damage in traumatic brain injury and stroke where cerebrospinal C-tau levels are correlated with patient clinical outcome. These data suggest that C-tau proteolysis may prove a reliable species independent biomarker of neuronal degeneration regardless of source of injury.
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PMID:Quantification and localization of kainic acid-induced neurotoxicity employing a new biomarker of cell death: cleaved microtubule-associated protein-tau (C-tau). 1452 98

Mesenchymal stem cells can be expanded rapidly in vitro and differentiated into multiple mesodermal cell types. In addition, their differentiation into neuron-like cells expressing markers typical for mature neurons has been reported. We isolated human adipose tissue stromal cells (hATSCs) from human liposuction tissues and induced neural differentiation with azacytidine. Following neural induction, hATSCs changed toward neural morphology and displayed expression of MAP2 and GFAP. hATSCs, which were labeled with LacZ adenovirus, were injected into the lateral ventricle of the rat brain. Transplanted cells migrated to various parts of the brain, and ischemic brain injury by middle cerebral artery occlusion (MCAo) increased their migration to the injured cortex. Some of the transplanted cells expressed MAP2 and GFAP. Transplantation of hATSCs improved functional deficits in ischemic brain injury induced by MCAo. Intracerebral grafting of BDNF-transduced hATSCs significantly improved motor recovery of functional deficits in MCAo rats. These data indicate that transplanted hATSCs survive, migrate, and improve functional recovery after stroke and that genetically engineered hATSCs can express biologically active gene products and, therefore, can function as effective vehicles for therapeutic gene transfer to the brain.
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PMID:Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. 1455 65

Interleukin-1 receptor antagonist (IL-1ra) has been shown previously to have neuroprotective effects in animal models of stroke. The effects of chronic overexpression of human soluble IL-1ra (hsIL-1ra) were studied in a mouse model of permanent focal cerebral ischemia. A transgenic mouse strain (Tg hsIL-1ra+/-) has been developed using the promoter for glial fibrillary acidic protein (GFAP) to limit the overexpression to the CNS. Analysis of the neurological scores, infarct volume and edema formation revealed no differences between Tg hsIL-1ra+/- and wild-type (WT) mice. The cerebral ischemia resulted in pronounced astrocyte proliferation and microglial activation, as well as induction of inflammatory markers in both Tg hsIL-1ra+/- and WT mice, with no major differences between the two genotypes. Interestingly, hsIL-1ra expression in astrocytes was reduced in infarcted areas as compared to non-ischemic regions and sham-operated controls. In conclusion, transgenic overexpression of hsIL1-ra was not neuroprotective in this cerebral ischemia model, possibly due to insufficient levels for protection against the extensive lesion, or an up-regulation of compensatory inflammatory signals due to the lifetime blockade of IL-1 receptors.
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PMID:Effects of chronic overexpression of interleukin-1 receptor antagonist in a model of permanent focal cerebral ischemia in mouse. 1513 79

Astrocytes secrete cytokines and neurotrophic factors to neurons, consistent with a neurosupportive role for astrocytes. However, in ischemic or metabolic insults, the function of astrocytic gap junctions composed mainly from connexin43 (Cx43) remains controversial. We have previously shown that heterozygous Cx43 null mice subjected to middle cerebral artery occlusion exhibited significantly enhanced stroke volume and apoptosis compared to wild-type mice. In this study, we used mice in which the human GFAP promoter-driven cre transgene deletes the floxed Cx43 gene in astrocytes, excluding the effects from reduced Cx43 expression in many other cell types as well as astrocytes. We induced focal brain ischemia in mice lacking Cx43 in astrocytes [Cre(+)] and control littermates [Cre(-)]. Cre(+) mice showed a significantly increased stroke volume and enhanced apoptosis, detected by terminal dUTP nick-end labeling and caspase-3 immunostaining, compared to Cre(-) mice. Inflammatory response assessed by the microglial marker CD11b was amplified in the penumbra of Cre(+) mice compared to that of Cre(-) mice. Our results suggest that astrocytic gap junctions could be important for the regulation of neuronal apoptosis and the inflammatory response after stroke. These findings support the view that astrocytes play a critical role in neuroprotection during ischemic insults.
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PMID:Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. 1516 41

The regenerative capacity of the CNS is extremely limited. The reason for this is unclear, but glial cell involvement has been suspected, and oligodendrocytes have been implicated as inhibitors of neuroregeneration (Chen et al., 2000, GrandPre et al., 2000; Fournier et al., 2001). The role of astrocytes in this process was proposed but remains incompletely understood (Silver and Miller, 2004). Astrocyte activation (reactive gliosis) accompanies neurotrauma, stroke, neurodegenerative diseases, or tumors. Two prominent hallmarks of reactive gliosis are hypertrophy of astrocytic processes and upregulation of intermediate filaments. Using the entorhinal cortex lesion model in mice, we found that reactive astrocytes devoid of the intermediate filament proteins glial fibrillary acidic protein and vimentin (GFAP-/-Vim-/-), and consequently lacking intermediate filaments (Colucci-Guyon et al., 1994; Pekny et al., 1995; Eliasson et al., 1999), showed only a limited hypertrophy of cell processes. Instead, many processes were shorter and not straight, albeit the volume of neuropil reached by a single astrocyte was the same as in wild-type mice. This was accompanied by remarkable synaptic regeneration in the hippocampus. On a molecular level, GFAP-/-Vim-/- reactive astrocytes could not upregulate endothelin B receptors, suggesting that the upregulation is intermediate filament dependent. These findings show a novel role for intermediate filaments in astrocytes and implicate reactive astrocytes as potent inhibitors of neuroregeneration.
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PMID:Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. 1516 94

Protease-activated receptor-1 (PAR1) is a G-protein coupled receptor that is proteolytically activated by blood-derived serine proteases. Although PAR1 is best known for its role in coagulation and hemostasis, recent findings demonstrate that PAR1 activation has actions in the central nervous system (CNS) apart from its role in the vasculature. Rodent studies have demonstrated that PAR1 is expressed throughout the brain on neurons and astrocytes. PAR1 activation in vitro and in vivo appears to influence neurodegeneration and neuroprotection in animal models of stroke and brain injury. Because of increasing evidence that PAR1 has important and diverse roles in the CNS, we explored the protein localization and function of PAR1 in human brain. PAR1 is most intensely expressed in astrocytes of white and gray matter and moderately expressed in neurons. PAR1 and GFAP co-localization demonstrates that PAR1 is expressed on the cell body and on astrocytic endfeet that invest capillaries. PAR1 activation in the U178MG human glioblastoma cell line increased PI hydrolysis and intracellular Ca(2+), indicating that PAR1 is functional in human glial-derived tumor cells. Primary cultures of human astrocytes and human glioblastoma cells respond to PAR1 activation by increasing intracellular Ca(2+). Together, these results demonstrate that PAR1 is expressed in human brain and functional in glial tumors and cultures derived from it. Because serine proteases may enter brain tissue and activate PAR1 when the blood brain barrier (BBB) breaks down, pharmacological manipulation of PAR1 signaling may provide a potential therapeutic target for neuroprotection in human neurological disorders.
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PMID:Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. 1519 6

Acute phase of stroke is the focus of most experimental and clinical studies on cerebral ischaemia. The scarcity of data on remote changes led us to examine the morphological pictures of brains after ischaemic insults. We paid special attention to the white matter capillaries. We microscopically evaluated 10 brains of patients who died after one month to fourteen years after the ischaemic stroke. Morphological examinations involved the application of routine histological stains and immunohistochemical reactions with antibodies against human albumin, GFAP, macrophage antigen CD 68 and lectins (Ulex europaeus, Wheat Germ agglutinin and Bandeirea simplicifolia). The results showed a swelling of the endothelial cells and their invagination into the vessel lumen. Postapoplectic cavities and white matter spongiosis decreasing with increase in distance from the cavity were observed. Immunohistochemical study showed that there was no segmental immunoreactivity to lectins on the capillary wall. Immune reaction to albumin revealed protein extravasation to the rarefied brain parenchyma. Our results indicate that progressing damage of the white matter after ischaemia may be caused not only by degeneration of axons of neurones destroyed by stroke, but also by pathological changes in small blood vessels, especially in capillaries. Hence, vascular leukoencephalopathy is probably caused by arteriolar damage as well as by microangiopathy.
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PMID:Remote morphological changes in the white matter after ischaemic stroke. 1526 81

Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague-Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response.
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PMID:Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. 1529 66

Up-regulation of glial fibrillary acidic protein (GFAP) expression is often used as a surrogate marker of neuronal damage. We have created a transgenic mouse line that carries the luciferase gene under the transcriptional control of the mouse GFAP promoter. Biophotonic imaging was used to non-invasively detect the increase in GFAP expression after kainic acid induced neuronal cell death. We demonstrate that after kainic acid treatment, strong biophotonic signals were detected from the brain area. This correlated with both endogenous GFAP and luciferase RNA levels as well as with hippocampal cell death observed histologically. The transgenic mouse line will provide a powerful tool to dynamically monitor neuronal cell death in the living animal and will aid in the discovery and development of drugs to treat damage due to stroke and other neurodegenerative diseases.
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PMID:Non-invasive imaging of GFAP expression after neuronal damage in mice. 1533 Nov 55


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