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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zinc release is a primary mediator of neuronal death. Here we show that zinc-mediated death of neurons in vitro is dependent on nerve growth factor (NGF) stimulation and does not occur in response to exposure to leukemia inhibitory factor. NGF priming is regulated, not by the traditional neurotrophin death receptor, p75NTR, but by TrkA, in a protein- and mRNA synthesis-dependent manner. Furthermore, Trk signaling promotes raised free intracellular zinc, mediating neuronal death after extracellular application of zinc. Thus, regulators of Trk signaling provide attractive targets for future treatment of zinc-associated neurological diseases, including stroke, epilepsy and brain trauma.
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PMID:Zinc-mediated neuronal death is dependent on Trk activation. 1743 97

Growth factors and their respective receptors are key regulators during development and for homeostasis of the nervous system. In addition, changes in growth factor function, availability or downstream signaling is involved in many neuropathological disorders like Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke and brain tumours. Research of the recent years revealed that some growth factors, initially discovered as neural growth factors are also affecting blood vessels [e.g. nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF)]. Likewise, vascular growth factors, such as vascular endothelial growth factor (VEGF), which was previously described as an endothelial cell specific mitogen, also affect neural cells. The discovery of shared growth factors affecting the vascular and the nervous system is of relevance for potential therapies of vascular and neurological diseases. This review aims to give an overview about the growing field of common growth factors and receptors within the two different networks.
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PMID:Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. 1749 93

Chronic stress and increased sympathetic nerve activity have been associated with cardiovascular disorders such as hypertension, myocardial infarction and stroke. The aim of this study was to investigate the role of nerve growth factor (NGF) on the expression of tyrosine hydroxylase (TH), vascular-endothelial growth factor (VEGF) and leptin receptor (OB-R) in brain, adrenal and cardiovascular tissues of adult male and female mice following a chronic stress procedure. It was found that daily restraint for 10 consecutive days alters TH levels in hypothalamic and brainstem areas related to sympathetic activation, in both male and female mice. Chronic stress procedure also modifies heart and aorta VEGF levels in male mice, and adrenal glands TH in female mice. The NGF administration in stressed mice reverted the stress-induced up-regulation of TH levels in male and female mice hypothalamic nuclei and in male locus coeruleus. Administration of NGF in stressed animals also down-regulated OB-R levels in the hypothalamus of both male and female mice and in the female aorta. Our findings indicate that repeated restraint in mice has an effect on TH and VEGF protein content at different brain and peripheral sites involved in the sympathetic and cardio-vascular response to stressful stimuli. NGF administration is able to counteract some of these stress-induced changes. Since NGF is known to be up-regulated during stress, a possible functional significance of our observations is that the circulating NGF released during and following stress may serve to prevent possible deficits and/or damage linked to stress-induced sympathetic and cardiovascular activation.
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PMID:Repeated restraint and nerve growth factor administration in male and female mice: effect on sympathetic and cardiovascular mediators of the stress response. 1828 16

AIT-082 (an analog of hypoxanthine) is an orally-active nerve growth factor (NGF) agonist under development by NeoTherapeutics as a potential treatment for Alzheimer's disease (AD), stroke and motor neuron disease. A phase II safety and efficacy trial in AD, originally scheduled to begin in the summer of 1997 [283677], began in May 1998 [286975,285562]. The study will enroll more than 60 AD patients [286975]. In February 1998, NeoTherapeutics began a phase I multiple-dose pharmacokinetic study of AIT-082 in 24 healthy elderly volunteers. Subjects of the phase I study will be administered AIT-082 once a day for 7 consecutive days at doses of 100 to 2000 mg per dose [279422]. A limited double-blind, placebo-controlled phase I/II trial in 10 AD patients commenced in Canada in the first quarter of 1997. Treatment with 4000 mg improved memory in 60% of the patients within 3 h, as determined by the word recall test. A decrease in memory was observed in 80% of placebo-treated patients [257132]. A phase I US trial, conducted by the Alzheimer's Disease Cooperative Study, with funding from the National Institute of Aging, began in July 1997. AIT-082 was administered to eight healthy, elderly volunteers as part of an escalating single-dose study. Oral administration of AIT-082 was well-tolerated at high doses [284325] AIT-082 also enhanced memory function in both young adult and aged mice within 2 h of oral administration. Prophylactic treatment prevented or delayed the onset of age-induced memory deficits in mice when administered in drinking water. When memory impairment was produced by brain lesions, the drug restored memory performance and increased the genetic expression of neurotrophin-3 (NT-3), a natural protein growth factor associated with nerve cell function [284325]. AIT-082 appears to have at least three effects on the growth of PC-12 cells in culture. Firstly, it stimulates outgrowth of neurites, secondly it potentiates the growth effects of neurotrophin, and thirdly, it stimulates the synthesis of certain neurotrophins (nerve growth factor, neurotrophin-3 and fibroblast growth factor) and pleiotrophins by astrocytes. These progrowth mechanisms are thought to form the basis of the ability of AIT-082 to restore and prevent age-related working memory deficits in mice [195438]. In October 1997, further preclinical results were presented, demonstrating that treatment with AIT-082 produced an increase in neurotrophic factors following spinal cord injury in rats. This study was conducted at NeoTherapeutics and McMaster University, and was partially funded by the Amyotrophic Lateral Sclerosis Society of Canada. After 7 days of treatment, rats with spinal cord injuries showed an increase in the levels of CNTF and BDNF, naturally occurring growth factors in the spinal cord [267514].
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PMID:AIT-082 NeoTherapeutics Inc. 1846 24

Human umbilical cord blood (HUCB) is a valuable source for cell therapy since it confers neuroprotection in stroke animal models. However, the responsible sub-populations remain to be established and the mechanisms involved are unknown. To explore HUCB neuroprotective properties in a PC12 cell-based ischemic neuronal model, we used an HUCB mononuclear-enriched population of collagen-adherent cells, which can be differentiated in vitro into a neuronal phenotype (HUCBNP). Upon co-culture with insulted-PC12 cells, HUCBNP conferred approximately 30% neuroprotection, as evaluated by decreased lactate dehydrogenase and caspase-3 activities. HUCBNP decreased by 95% the level of free radicals in the insulted-PC12 cells, in correlation with the appearance of antioxidants, as measured by changes in the oxidation-reduction potential of the medium using cyclic-voltammetry. An increased level of nerve growth factor (NGF), vascular endothelial growth factor and basic fibroblast growth factor in the co-culture medium was temporally correlated with a -medium neuroprotection effect, which was partially abolished by heat denaturation. HUCBNP-induced neuroprotection was correlated with changes in gene expression of these neurotrophic factors, while blocked by K252a, an antagonist of the TrkA/NGF receptor. These findings indicate that HUCBNP-induced neuroprotection involves antioxidant(s) and neurotrophic factors, which, by paracrine and/or autocrine interactions between the insulted-PC12 and the HUCBNP cells, conferred neuroprotection.
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PMID:Neuroprotection by cord blood neural progenitors involves antioxidants, neurotrophic and angiogenic factors. 1907 Jun 17

Although ex vivo culture expansion is necessary to use autologous mesenchymal stem cells (MSCs) in treating stroke patients, and several researchers have utilized culture-expanded cells in their studies, the effects of culture expansion on neurogenesis and trophic support are unknown. Thus, we evaluated the impact of the passage of MSCs on their effects in a rat stroke model. The i.v. application of ex vivo-cultured human MSCs, earlier (passage 2) or later passage (passage 6), was performed in a rat stroke model. Behavioral tests, immunohistochemical studies, and quantitative analysis using the CAST-grid system were performed to evaluate the degree of neurogenesis. We also evaluated the levels of trophic factors in both control and MSC-treated rat brain extract. Compared to rats that received later-passage human MSCs, behavioral recovery and neurogenesis as revealed by bromodeoxyuridine staining were more pronounced in rats that received earlier-passage human MSCs (p < 0.01 in both cases). Double staining showed that most of the endogenous neuronal progenitor cells, but few human MSCs, expressed neuronal and glial phenotypes. Tissue levels of trophic factors, including glial cell line-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were higher in earlier-passage MSC-treated brains than in control or later-passage MSC-treated brains (p < 0.01 in all cases). Our results indicate that ischemia-induced neurogenesis was enhanced by the i.v. administration of human MSCs. The effects were more pronounced with earlier-passage than with later-passage human MSCs, which may be related to the differential capacity in trophic support, depending on their passage.
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PMID:Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. 1917 41

Neurotrophins are critical for the survival of neurons during development and insufficient access to neurotrophins later in life may contribute to the loss of neurons in neurodegenerative disease, spinal cord injury, and stroke. The prolyl hydroxylase inhibitors ethyl 3,4-dihydroxybenzoic acid (DHB) and dimethyloxalylglycine (DMOG) were shown to inhibit cell death in a model of neurotrophin deprivation that involves depriving sympathetic neurons of nerve growth factor (NGF). Here we show that treatment with DMOG or DHB reverses the decline in 2-deoxyglucose uptake caused by NGF withdrawal and suppresses the NGF deprivation-induced accumulation of reactive oxygen species. Neither DMOG nor DHB prevented death when NGF deprivation was carried out under conditions of glucose starvation, and both compounds proved toxic to NGF-maintained neurons deprived of glucose, suggesting that their survival-promoting effects are mediated through the preservation of glucose metabolism. DHB and DMOG are well known activators of hypoxia-inducible factor (HIF), but whether activation of HIF underlies their survival-promoting effects is not known. Using gene disruption and RNA interference, we provide evidence that DMOG and, to a lesser extent, DHB require HIF-2alpha expression to inhibit NGF deprivation-induced death. Furthermore, suppressing basal HIF-2alpha expression, but not HIF-1alpha, in NGF-maintained neurons is sufficient to promote cell death. These results implicate HIF-2alpha in the neuroprotective mechanisms of prolyl hydroxylase inhibitors and in an endogenous cell survival pathway activated by NGF in developing neurons.
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PMID:Prolyl hydroxylase inhibitors depend on extracellular glucose and hypoxia-inducible factor (HIF)-2alpha to inhibit cell death caused by nerve growth factor (NGF) deprivation: evidence that HIF-2alpha has a role in NGF-promoted survival of sympathetic neurons. 1920 94

Cognitive impairments, including spatial memory and learning deficiencies, are common after ischemic stroke. Estrogen substitution improves cognitive functions in post-menopausal women and ovariectomized rodents, partially through induction of neuroplasticity in the hippocampal formation. Post-ischemic housing of male rats in an enriched environment (EE) improves functional outcome, without changing infarct volume. We hypothesized that 17beta-estradiol combined with an EE would accelerate cognitive recovery after focal brain ischemia in ovariectomized rats and that recovery would be related to altered expression of nerve growth factor-induced gene (NGFI)-A in the hippocampus. 17beta-estradiol or placebo pellets were implanted 6 h after transient middle cerebral artery occlusion. Two days later, rats were placed in an EE or a deprived environment (DE) for 6 weeks. At 5 weeks after middle cerebral artery occlusion, 17beta-estradiol-treated rats housed in an EE showed improvements in cognitive function (i.e. shorter latency and path in the Morris water maze task) compared with placebo-treated animals housed in an EE. Furthermore, beneficial effects on latency and path were observed when comparing EE-housed vs. DE-housed 17beta-estradiol-treated rats. When comparing 17beta-estradiol-treated EE-housed rats vs. placebo-treated DE-housed rats, pronounced effects on latency and path were observed. Infarct volumes did not differ between groups. 17beta-estradiol-treated EE-housed rats had significantly higher NGFI-A mRNA expression bilaterally in the cornu ammonis 1 region and in the ipsilateral dentate gyrus of the hippocampus, compared with placebo-treated EE-housed rats. In conclusion, 17beta-estradiol treatment combined with an EE improved recovery of cognitive function after experimental brain ischemia, putatively through the upregulation of NGFI-A in hippocampal subregions.
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PMID:17beta-estradiol and enriched environment accelerate cognitive recovery after focal brain ischemia. 1930 56

Brain injury from ischemic stroke can be devastating, but full brain restoration is feasible. Time until treatment is critical; rapid rate of injury progression, logistical and personnel constraints on neurological and cardiovascular assessment, limitations of recombinant tissue plasminogen activator (rtPA) for thrombolysis, anticoagulation and antiplatelet interventions, and neuroprotection all affect outcome. Promising acute neuroprotectant measures include albumin, magnesium, and hypothermia. Long-term hyperbaric oxygen therapy (HBOT) is safe and holds great promise. Eicosanoid and cytokine down-regulation by omega-3 nutrients docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may help quench stroke inflammation. C-reactive protein (CRP), an inflammatory biomarker and stroke-recurrence predictor, responds favorably to krill oil (a phospholipid-DHA/EPA-astaxanthin complex). High homocysteine (Hcy) is a proven predictor of stroke recurrence and responds to folic acid and vitamin B12. Vitamin E may lower recurrence for individuals experiencing high oxidative stress. Citicoline shows promise for acute neuroprotection. Glycerophosphocholine (GPC) is neuroprotective and supports neuroplasticity via nerve growth factor (NGF) receptors. Stem cells have shown promise for neuronal restoration in randomized trials. Endogenous brain stem cells can migrate to an ischemic injury zone; exogenous stem cells once transplanted can migrate (home) to the stroke lesion and provide trophic support for cortical neuroplasticity. The hematopoietic growth factors erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have shown promise in preliminary trials, with manageable adverse effects. Physical and mental exercises, including constraint-induced movement therapy (CIMT) and interactive learning aids, further support brain restoration following ischemic stroke. Brain plasticity underpins the function-driven brain restoration that can occur following stroke.
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PMID:Integrated brain restoration after ischemic stroke--medical management, risk factors, nutrients, and other interventions for managing inflammation and enhancing brain plasticity. 1936 91

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.
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PMID:Review of lithium effects on brain and blood. 1952 43


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