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

Moderate hypothermia and application of brain-derived neurotrophic factor (BDNF) have separately been identified as neuroprotective strategies in experimental cerebral ischemia. To assess their separate and combined effects on striatal glutamate release in the hyperacute phase of stroke, we inserted microdialysis probes into the striatum of rats 2 h before permanent middle cerebral artery occlusion (MCAO). The animals (N = 28) were randomly assigned to one of four treatment strategies commencing 30 min after MCAO: (1) hypothermia at 33 degrees C (n = 7); (2) intravenous BDNF infusion [300 microg/(kg/h) for 2 h, n = 7]; (3) combination of hypothermia and BDNF (n = 7); (4) control group (saline, n = 7). Infarct size at 5 h after MCAO was assessed with the silver-staining method. Total infarct volume was significantly reduced in the hypothermia (202.7 +/- 3.5 mm(3), P = 0.0002) and BDNF group (206.5 +/- 6.9 mm(3), P = 0.0006) as compared to control group (254.4 +/- 9.3 mm(3)). In the combination group, infarct size was further reduced with overall significance in post hoc tests (157.3 +/- 6.2 mm(3), P < 0.0001). Postischemic glutamate concentrations in the control group constantly remained significantly higher than in all other treatment groups. At 255 and 270 min after MCAO, striatal glutamate in the combination group decreased significantly more than in animals treated with hypothermia or BDNF alone.Combining hypothermia and BDNF therapy in the acute stage of ischemia has a synergistic effect in attenuating striatal glutamate release and reducing early infarct size.
 ...
PMID:Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke. 1473 12

Cyclic AMP response element binding protein (CREB) is a transcription factor expressed constitutively primarily in neurons and is activated by phosphorylation at Ser(133) residue. CREB mediates expression of several neuroprotective proteins, including B-cell CLL/lymphoma 2 (BCL-2) and brain-derived neurotrophic factor (BDNF). Although phosphorylation of CREB after ischemia has been investigated extensively, CRE-mediated gene transcription after ischemia is not as well studied. We investigated temporal changes in CRE-mediated gene transcription in the cerebral cortex after focal ischemia in transgenic mice with a CRE-lacZ reporter gene. In the ischemic core, X-gal-positive cells, which reflected expression of the CRE-lacZ reporter gene, were observed rarely at any time point, though transient phosphorylation of CREB was detected. In contrast, the peri-infarct area showed a persistent increase in the number of X-gal-positive cells, of which more than half were positive for neuronal nuclei (NeuN). Our results suggest that CRE-mediated gene transcription, the pattern of which is not always consistent with that of CREB phosphorylation, occurs primarily in neurons in the peri-infarct area after focal cerebral ischemia and may be a neuroprotective response against ischemic insult.
 ...
PMID:CRE-mediated gene transcription in the peri-infarct area after focal cerebral ischemia in mice. 1474 53

Examination of the clinical therapeutic efficacy of using bone marrow stromal cells, including mesenchymal stem cells (MSC), has recently been the focus of much investigation. MSC were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we transfected telomerized human MSC with the BDNF gene using a fiber-mutant F/RGD adenovirus vector and investigated whether these cells contributed to improved functional recovery in a rat transient middle cerebral artery occlusion (MCAO) model. BDNF production by MSC-BDNF cells was 23-fold greater than that seen in uninfected MSC. Rats that received MSC-BDNF showed significantly more functional recovery than did control rats following MCAO. Specifically, MRI analysis revealed that the rats in the MSC-BDNF group exhibited more significant recovery from ischemia after 7 and 14 days. The number of TUNEL-positive cells in the ischemic boundary zone was significantly smaller in animals treated with MSC-BDNF compared to animals in the control group. These data suggest that MSC transfected with the BDNF gene may be useful in the treatment of cerebral ischemia and may represent a new strategy for the treatment of stroke.
 ...
PMID:BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. 1475 3

Sendai virus (SeV) vector-mediated gene delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) prevented the delayed neuronal death induced by transient global ischemia in gerbils, even when the vector was administered several hours after ischemia. Intraventricular administration of SeV vector directed high-level expression of the vector-encoded neurotrophic factor genes, which are potent candidates for the treatment of neurodegenerative diseases. After occlusion of the bilateral carotid arteries of gerbils, SeV vector carrying GDNF (SeV/GDNF), NGF (SeV/NGF), brain-derived neurotrophic factor (SeV/BDNF), insulin-like growth factor-1 (SeV/IGF-1) or vascular endothelial growth factor (SeV/VEGF) was injected into the lateral ventricle. Administration of SeV/GDNF, SeV/NGF or SeV/BDNF 30 min after the ischemic insult effectively prevented the delayed neuronal death of the hippocampal CA1 pyramidal neurons. Furthermore, the administration of SeV/GDNF or SeV/NGF as late as 4 or 6 h after the ischemic insult also prevented the death of these neurons. These results indicate that SeV vector-mediated gene transfer of neurotrophic factors has high therapeutic potency for preventing the delayed neuronal death induced by transient global ischemia, and provides an approach for gene therapy of stroke.
 ...
PMID:Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils. 1496 Oct 67

Compared to young rats, old age increases susceptibility and caloric restriction decreases susceptibility for the loss of retinal ganglion cells and displaced amacrine cells following retinal ischemia/reperfusion. In retinas of old animals before ischemia, reactive gliosis, including activation of Muller cells, microglia and astrocytes, is increased compared to retinas from young and old/caloric restricted animals. Post-ischemia, the existing reactive gliosis in retinas of old animals is not neuroprotective and the reactive gliosis is even further increased in old animals compared to young or old/caloric restricted animals. In retinas from old/caloric restricted animals, inducible heat shock protein-70 and brain-derived neurotrophic factor increased more markedly after ischemia/reperfusion compared to retinas from young and old animals. Thus, compared to retinas in young animals, neurons of old animals may be more susceptible to cell death by secondary glial mechanisms after retinal ischemia/reperfusion. Caloric restriction in old animals is neuroprotective against damage in the retina following ischemia, perhaps by suppressing glial activity and by the neuroprotective effects of inducible heat shock protein-70 and brain-derived neurotrophic factor.
 ...
PMID:Neuronal susceptibility to damage: comparison of the retinas of young, old and old/caloric restricted rats before and after transient ischemia. 1501 70

We studied the expression of brain-derived neurotrophic factor (BDNF) immunoreactivity and mRNA in the ischemia-vulnerable cerebral hippocampal CA1 and cortical areas after permanent occlusion of bilateral internal carotid arteries. Four groups of rats were studied, including 1) young normotensive Wistar-Kyoto (WKY) rats, 2) aged normotensive WKY rats, 3) young spontaneous hypertensive rats (SHR), and 4) aged SHR. Each group contained rats from sham operation and 1 week, 4 weeks, and 8 weeks after cerebral ischemia (n = 3-5 at each time point). Hematoxylin and eosin staining and in situ apoptosis detection showed no neuronal damage from 1 week to 8 weeks in all the ischemic rats. Immunohistochemistry and Western blot showed that BDNF immunoreactivity increased only at 1 week in the CA1 area of young WKY rats (P < .001) and SHR (P = .002) and decreased only at 8 weeks in the cortical area of aged WKY rats (P = .02). In situ hybridization and TaqMan real-time RT-PCR showed that BDNF mRNA decreased consistently from 1 week to 8 weeks in both CA1 and cortical areas in young SHR (P < .05 and P < .01, respectively) and in aged WKY rats (P < .01 and P < .05, respectively) but was not changed in young WKY rats or aged SHR (P > .05) compared with the sham-operated rats. Our study demonstrates an expression disparity of BDNF immunoreactivity and mRNA in the hippocampal CA1 and cortical areas, especially in the young SHR and aged WKY rats after mild cerebral ischemia. Our study suggests that, under permanent occlusion of bilateral internal carotid arteries, aging and the level of blood pressure may have influence on the expression of BDNF.
 ...
PMID:Expression of brain-derived neurotrophic factor immunoreactivity and mRNA in the hippocampal CA1 and cortical areas after chronic ischemia in rats. 1513 29

Preconditioning the rat brain with spreading depression for 48 h induces potent ischemic tolerance (infarct tolerance) after an interval of 12-15 days, consequently reducing the infarcted lesion size in the acute phase following focal cerebral ischemia. However, persistence of the morphological and functional neuroprotection has not yet been proven. We tested whether tolerance-derived neuroprotection against focal cerebral ischemia persists or merely delays the progress of cerebral infarction. Prolonged spreading depression was induced in mice by placing a depolarized focus with intracerebral microinfusion of KCl for 24 h; after intervals of 3, 6, 9 or 12 days, temporary focal ischemia was imposed. In the analysis of the infarcted lesion volume 24 h after ischemia, groups with 6 or 9 day interval demonstrated significantly smaller lesion volume compared to time-matched vehicle control group (P=0.002). Significant reduction in cerebral infarction was also observed at the chronic phase, namely 14 days after ischemia (33% reduction) (P=0.021) accompanied with less severe neurological deficits (38% reduction) (P=0.020). Using this technique, we also investigated if the mice with targeted disruption of a single BDNF allele (heterozygous BDNF-deficient mice) can gain the same potency of tolerance as the wild mice. In the result on infarcted lesion volumes following temporary focal ischemia, potent tolerance developed in the wild type (35% reduction) (P=0.007) but not in the heterozygous BDNF-deficient mice (<19% reduction) (P=0.155), indicating that BDNF expression level following spreading depression is contributing to infarct tolerance development.
 ...
PMID:Spreading depression induces long-lasting brain protection against infarcted lesion development via BDNF gene-dependent mechanism. 1530 52

FGF-2, a potent multifunctional and neurotrophic growth factor, is widely expressed in the brain and upregulated in cerebral ischemia. Previous studies have shown that intraventricularly or systemically administered FGF-2 reduces the size of cerebral infarcts. Whether endogenous FGF-2 is beneficial for the outcome of cerebral ischemia has not been investigated. We have used mice with a null mutation of the fgf2 gene to explore the relevance of endogenous FGF-2 in brain ischemia. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCAO). We found a 75% increase in infarct volume in fgf2 knock-out mice versus wild type littermates (P < 0.05). This difference in the extent of ischemic damage was observed after 24 h, and correlated with decreased viability in fgf2 mutant mice following MCA occlusion. Increased infarct volume in fgf2 null mice was associated with a loss of induction in hippocampal BDNF and trkB mRNA expression. These findings indicate that signaling through trkB may contribute to ameliorating brain damage following ischemia and that bdnf and trkB may be target genes of FGF-2. Together, our data provide the first evidence that endogenous FGF-2 is important in coping with ischemic brain damage suggesting fgf2 as one crucial target gene for new therapeutic strategies in brain ischemia.
 ...
PMID:Enlarged infarct volume and loss of BDNF mRNA induction following brain ischemia in mice lacking FGF-2. 1538 Apr 77

In the adult hippocampus, neurogenesis proceeds in the subgranular zone (SGZ) of the dentate gyrus (DG), but not in the cornu Ammonis (CA). Recently, we demonstrated in monkeys that transient brain ischemia induces an increase of the neuronal progenitor cells in the SGZ, but not in CA1, in the second week after the insult. To identify the origin of primary neuronal progenitors in vivo, we compared the postischemic monkey DG and CA1, using light and electron microscopy, focusing on specific phenotype markers, as well as the expression of neurotrophic factors. Laser confocal microscopy showed that 1-3% of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the SGZ after 2-96 h labeling were also positive for neuronal markers such as TUC4, betaIII tubulin, and NeuN on days 9 and 15. In contrast, despite the presence of numerous BrdU-positive cells, CA1 showed no neurogenesis at any time points, and all the progenitors were positive for glial markers: Iba1 or S-100beta on days 4, 9, and 15. Highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive cells were abundant in the SGZ, but were absent in CA1. On day 9, most of the immature neurons positive for betaIII-tubulin in SGZ showed an increase in PSA-NCAM immunoreactivity. The immunoreactivity of brain-derived neurotrophic factor (BDNF) was abundant at the vascular adventitia of the SGZ, but was absent at the adventitia of CA1. BrdU-positive progenitor cells were frequently seen in the vicinity of proliferating blood vessels. Ultrastructural analysis indicated that most of the neuronal progenitor cells and microglia originated from the pericytes of capillaries and/or adventitial cells of arterioles (called vascular adventitia). The detaching adventitial cells showed mitotic figures in the perivascular space, and the resultant neuronal progenitor cells made contact with dendritic spines associated with synaptic vesicles or boutons. These data implicate the vascular adventitia as a novel potential source of neuronal progenitor cells in the postischemic primate SGZ.
 ...
PMID:Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia. 1538 56

The goal of neuroprotection in glaucoma treatment is to employ agents that prevent or delay apoptosis of retinal ganglion cells (RGC) and facilitate regeneration of already damaged calls. The following contribution discusses the mechanisms of RGC death and current status of neuroprotective in vivo studies and investigations on cell cultures and animal models. Discussions on the etiopathogenesis of PCOAG center on elevated IOP and ocular disorders of vascular function. The mechanisms of axonal damage induced by ischemia are explained and the resultant possible neuroprotective effect mechanisms are discussed (Na(+) or Ca(2+) channel blockers, role of reactive astrocytes). Substitution of axonal survival factors and especially the role of BDNF are described. Glutamate excitotoxicity also plays a role in glaucomatous antegrade RGC death. Relevant questions and possible therapeutic approaches are discussed. The three phases of apoptosis cascade and the key role of mitochondria in the insult-induced apoptosis are considered as well as the still relatively unexplored possibilities of RGC regeneration. Finally, perspectives of neuroprotective treatment of PCOAG are presented.
 ...
PMID:[Mechanisms of neuroprotection against glaucoma]. 1549 Jan 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>