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)

The transport of brain derived neurotrophic factor (BDNF) across the blood-brain barrier (BBB) is negligible in normal conditions. However, BDNF might pass through the BBB when BBB is disrupted by a pathological condition such as stroke. This migration of BDNF through the BBB might be important during post-ischemic phase since BDNF can exert a protective action in the site of lesion. This study aimed to investigate plasma levels of BDNF in the acute phase of stroke in humans. Serial venous blood samples were taken in ten patients with acute stroke at the admission to the Stroke Unit and on the following 4 days. In the same samples we also evaluated the plasma levels of S100beta protein, a marker of BBB disruption. There was no significant change in BDNF plasma levels in our patients, even in the presence of a pronounced BBB dysfunction, as demonstrated by a significant increase of S100beta protein concentrations at days 2 and 3 after stroke. Our data, though indirectly, suggest that there is no significant increase in endogenous extracellular BDNF after a stroke in humans.
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PMID:BDNF plasma levels in acute stroke. 1759 May 13

Oral administration of red ginseng powder before but not after transient forebrain ischemia prevents delayed neuronal death in gerbils. One neuroprotective molecule within red ginseng powder is ginsenoside Rb(1). The mechanism of action(s) of ginsenoside Rb(1) remains to be determined. We performed intracerebroventricular infusion of 0.6 microg/d ginsenoside Rb(1) before or after permanent occlusion of the left middle cerebral artery in stroke-prone spontaneous hypertensive rats. Ginsenoside Rb(1) significantly decreased escape latency on repeated trials of the Morris water maze test, throughout the first to fourth trial days at 2 and 4 weeks after MCA occlusion (P<.05, P<.01 or P<.001). The ratio of the infarcted area to the left hemispheric area in the groups treated with 0.6 microg/d of ginsenoside Rb(1) was significantly smaller than that in the saline-treated ischemic group (P<.05 or P<.001). The continuous infusion of ginsenoside Rb(1) (0.06 microg/d) was less effective and the other doses examined were ineffective in ameliorating ischemia-induced image navigation disability and reducing cortical infarct size. There were significant differences in neuron numbers in the ventroposterior thalamic nucleus and in the left-to-right ratio of the thalamic area between the saline-infused ischemic group and the ginsenoside Rb(1)-treated ischemic group (P<.05 or P<.01). Moreover, ginsenoside Rb(1) at concentrations of 0.1 to 100 fg/mL (0.09 to 90 fM), facilitated neurite extension and rescued cortical neurons from lethal damage caused by the free radical-promoting agent FeSO(4), in vitro (P<.05 or P<.01). These findings suggest that ginsenoside Rb(1) protects the cerebral cortex against lethal ischemic damage possibly by acting as a neurotrophic factor-like agent and by scavenging free radicals, which are overproduced in situ during and after brain ischemia. The final link between the in vivo neuroprotective action and the in vitro neurotrophic and antioxidant activities of ginsenoside Rb(1) remains to be determined.
J Stroke Cerebrovasc Dis
PMID:Ginsenoside Rb(1) prevents image navigation disability, cortical infarction, and thalamic degeneration in rats with focal cerebral ischemia. 1789 50

The sigma1 receptor is an intracellular molecule that shares no homology with any mammalian proteins. sigma1 receptors normally localize at the endoplasmic reticulum and regulate a variety of signal transductions including intracellular Ca2+ dynamics and neurotrophic factor signaling. In the brain, sigma1 receptors are known to regulate the activity of diverse ion channels via protein-protein interactions. Accumulated evidences strongly indicate that the activation/upregulation of sigma1 receptors promotes the neuronal differentiation as well as a robust antiapoptotic action. In animals, sigma1 receptor agonists exhibit an antidepressant-like action. Furthermore, the agonists enhanced neuronal survival eventhough they were administered several hours after a brain ischemia. Thus, primary clinical targets of sigma1 receptor ligands are proposed to include stroke, neurodegenerative disorders and depression. Ligands for the sigma1 receptor may constitute a new class of therapeutic drugs targeting an endoplasmic reticular protein.
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PMID:An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma 1 receptor ligand. 1807 69

Glial-derived neurotrophic factor (GDNF) is a neurotrophin that could be developed as a neurotherapeutic for Parkinson's disease, stroke, and motor neuron disease. However, GDNF does not cross the blood-brain barrier (BBB). Human GDNF was re-engineered by fusion of the mature GDNF protein to the carboxyl terminus of the chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb-GDNF fusion protein is bi-functional, and both binds the HIR, to trigger receptor-mediated transport across the BBB, and binds the GDNF receptor (GFR)-alpha1, to activate GDNF neuroprotection pathways behind the BBB. COS cells were dual transfected with the heavy chain (HC) and light chain fusion protein expression plasmids, and the HC of the fusion protein was immunoreactive with antibodies to both human IgG and GDNF. The HIRMAb-GDNF fusion protein bound with high affinity to the extracellular domain of both the HIR, ED(50) = 0.87 +/- 0.13 nM, and the GFRalpha1, ED(50) = 1.68 +/- 0.17 nM. The HIRMAb-GDNF fusion protein activated luciferase gene expression in human neural SK-N-MC cells dual transfected with the c-ret kinase and a luciferase reporter gene under the influence of the rat tyrosine hydroxylase promoter, and the ED(50), 1.68 +/- 0.45 nM, was identical to the ED(50) in the GFRalpha1 binding assay. The fusion protein was active in vivo in a rat middle cerebral artery occlusion model, where the stroke volume was reduced 77% (P < 0.001). In conclusion, these studies describe the re-engineering of GDNF, to make this neurotrophin transportable across the human BBB.
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PMID:GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier. 1808 Mar 33

Cells of the central nervous system were once thought to be incapable of regeneration. This dogma has been challenged in the last decade with studies showing new, migrating stem cells in the brain in many rodent injury models and findings of new neurones in the human hippocampus in adults. Moreover, there are reports of bone marrow-derived cells developing neuronal and vascular phenotypes and aiding in repair of injured brain. These findings have fuelled excitement and interest in regenerative medicine for neurological diseases, arguably the most difficult diseases to treat. There are numerous proposed regenerative approaches to neurological diseases. These include cell therapy approaches in which cells are delivered intracerebrally or are infused by an intravenous or intra-arterial route; stem cell mobilization approaches in which endogenous stem and progenitor cells are mobilized by cytokines such as granulocyte colony stimulatory factor (GCSF) or chemokines such as SDF-1; trophic and growth factor support, such as delivering brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) into the brain to support injured neurones; these approaches may be used together to maximize recovery. While initially, it was thought that cell therapy might work by a 'cell replacement' mechanism, a large body of evidence is emerging that cell therapy works by providing trophic or 'chaperone' support to the injured tissue and brain. Angiogenesis and neurogenesis are coupled in the brain. Increasing angiogenesis with adult stem cell approaches in rodent models of stroke leads to preservation of neurones and improved functional outcome. A number of stem and progenitor cell types has been proposed as therapy for neurological disease ranging from neural stem cells to bone marrow derived stem cells to embryonic stem cells. Any cell therapy approach to neurological disease will have to be scalable and easily commercialized if it will have the necessary impact on public health. Currently, bone marrow-derived cell populations such as the marrow stromal cell, multipotential progenitor cells, umbilical cord stem cells and neural stem cells meet these criteria the best. Of great clinical significance, initial evidence suggests these cell types may be delivered by an allogeneic approach, so strict tissue matching may not be necessary. The most immediate impact on patients will be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.
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PMID:Stem cells and neurological diseases. 1818 51

Neurotrophic factors comprise a broad family of secreted proteins that have growth promoting, survival promoting and differentiation inducing activities. Disruption of neurotrophic factor signalling is a characteristic of many central and peripheral nervous system disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and peripheral neuropathy and pain. It follows that treating patients with neurotrophic factors might be beneficial in a range of neurological diseases. However, the promising results seen in animal models of disease have not translated well into clinical trials due to the poor pharmacokinetics associated with the intact proteins, in particular, their short in vivo half-life, low blood brain barrier permeability, limited diffusion, and undesirable effects through multiple receptor interactions. This has been the main motivation for the design of small molecule modulators of the neurotrophic factor pathways. The review gives a brief survey of the various strategies to design mimetics that have been reported in the literature with special emphasis on the tandem repeat peptide agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.
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PMID:Tandem repeat peptide strategy for the design of neurotrophic factor mimetics. 1828 37

This review article discusses recent progress on the use of teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N cells, also called hNT cells) as graft source for cell transplantation in stroke. Laboratory evidence has demonstrated the therapeutic potential of NT2N cells in stroke therapy. Phase I and II clinical trials have shown the cells' feasibility, safety and tolerability profiles in stroke patients. Despite these novel features of NT2N cells, the transplantation regimen remains to be optimized. Moreover, determining the mechanisms underlying the grafts' beneficial effects, specifically demonstrating functional synaptic connections between host brain and NT2N cell grafts, warrants further examination. The major limiting factor for initiating a large clinical trial is the cells' highly potent proliferative property due to their cancerous origin, thereby raising the concern that these cells may revert to a neoplastic state over time after transplantation. To this end, we explored a proof-of-concept "retroviral" strategy to further establish the post-mitotic status of NT2N cells by transfecting these cells with the transcription factor Nurr1, in addition to the standard treatment with retinoic acid and mitotic inhibitors. This new cell line NT2N.Nurr1 displays an expedited neuronal commitment and secretes a high level of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF), and when transplanted into the rodent stroke brain expressed neuronal phenotype and reduced behavioral impairments which are comparable, if not more robust, than those produced by NT2N cells. Such highly potent neuronal lineage commitment and neurotrophic factor secretory function of NT2.Nurr1 cells make them an appealing graft source for transplantation therapy.
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PMID:Neural progenitor NT2N cell lines from teratocarcinoma for transplantation therapy in stroke. 1851 79

The effect of acupuncture on motor recovery after stroke continues to be debated. This animal study was designed to determine whether acupuncture improves motor function following experimentally induced cerebral ischemia. In addition, we studied whether the outcome of motor function was associated with the expression of BDNF (brain derived neurotrophic factor), trkB (receptor, trkB) and infarct volume. Cerebral ischemia was induced by permanent middle cerebral artery occlusion (MCAO) or MCAO plus bilateral vertebral artery occlusion in Sprague-Dawley rats. The groups studied were a control, treadmill exercise, electroacupuncture and a combined treatment group with both treadmill exercise and electroacupuncture (ExEA). On postoperative day 16, Western blot analysis for BDNF and trkB and estimation of infarct volume were performed. The motor behavior scores were measured 2 and 16-days postoperatively. Comparison of the motor scores among the groups showed that the motor scores in the exercise only group and ExEA group were higher than in the control group on postoperative day 16. No statistical significance was found among the groups in the Western blot analysis and the infarct volume. This study demonstrates no significant additional effect of electroacupuncture on the motor recovery in rats following mild cerebral ischemia during the early recovery stage. Further studies in a rat model with moderate to severe cerebral ischemia, assessment and reassessment for more extended periods after the cerebral ischemia will be required.
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PMID:Effect of electroacupuncture on motor recovery in a rat stroke model during the early recovery stage. 1904 35

Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.
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PMID:Glutamate and neurotrophic factors in neuronal plasticity and disease. 1907 69

Transforming growth factor-alpha (TGFalpha) is a powerful endogenous mitogen and neurotrophic factor, which has previously been shown to induce a massive proliferative response in the brains of Parkinson's disease model rats injured by an acute neurotoxic lesion. We now show that TGFalpha can also produce a massive proliferative response in rat brains subjected to stroke caused by a middle cerebral artery occlusion (MCAO), even when the growth factor is administered as late as 4 weeks after injury. This combination of stimuli provokes DNA synthesis, shown by 5'-bromo-2-deoxyuridine incorporation, throughout the ependymal layer and subventricular zone (SVZ) of the forebrain during the 4 weeks of growth factor administration. The newly generated cells migrate preferentially along and ventral to the corpus callosum (CC) and external capsule to the site of the injury where many of them differentiate into several site-appropriate neuronal phenotypes in association with near complete (99%) behavioral recovery. We conclude that the injury response of endogenous neural stem cells as well as behavioral recovery can be significantly enhanced by application of TGFalpha, and that this approach represents a potential therapeutic strategy for chronic stroke and other neurological damage in human patients.
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PMID:Transforming growth factor-alpha induces neurogenesis and behavioral improvement in a chronic stroke model. 1924 22


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