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

To obtain insight into the hemodynamics of abnormal cardiac development, a chick embryo model was recently developed in which a spectrum of double outlet right ventricle was induced with all-trans-retinoic acid. In Hamburger and Hamilton (HH) stage 34 white Leghorn chick embryos, we simultaneously measured dorsal aortic flow velocities with a 20 MHz pulsed Doppler velocity meter and vitelline artery blood pressures with a servonull system. These measurements were performed in embryos treated at HH stage 15 with 1 microgram of all-trans-retinoic acid (n = 47), or with the solvent DMSO (n = 15), and in control embryos (n = 21). After the wave form recordings were collected, all embryos were examined histologically. Embryos treated with all-trans-retinoic acid showed in 15 cases hearts with a rightward positioned aorta with an additional subaortic ventricular septal defect and 32 cases without septation abnormalities of the heart. The hemodynamic data were correlated with the morphology. Statistical comparison was performed between control and experimental values. There was no significant discrepancy in hemodynamics of sham-operated and control embryos. Heart rate, peak systolic and mean velocities, peak systolic and mean blood flows, and peak acceleration and stroke volume were reduced in embryos treated with all-trans-retinoic acid (p < 0.01). Furthermore, in the presence of a subaortic ventricular septal defect the diameter of the dorsal aorta was reduced. Pressure readings were not statistically significant. Our findings suggest that the hemodynamic changes are the result of a decrease in cardiac contraction force.
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PMID:Hemodynamic changes in HH stage 34 chick embryos after treatment with all-trans-retinoic acid. 749 57

Thrombomodulin (TM), a key cofactor of the TM-protein C pathway, is of major biologic significance for the antithrombotic properties of endothelial cells. Yet, there is uncertainty whether TM is expressed in brain and what mechanisms govern brain endothelial anticoagulant activity. In this study, bovine brain capillaries were used as an in vitro model of the blood-brain barrier to determine factors involved in the regulation of TM expression in cerebral vasculature. Quantitative competitive-polymerase chain reaction assay revealed significant regional differences in the amount of brain capillary TM mRNA, i.e., cortical > cerebellar > pontine, consistent with the reverse transcription-polymerase chain reaction findings in which the abundance of TM mRNA was analyzed relative to beta-actin mRNA. Regional differences in TM mRNA brain capillary level correlated well with differences in protein C activation. The TM mRNA and activity were not detectable in brain parenchyma. Pathogenic mediators of ischemic stroke, interleukin 1 beta (10 U/mL), and tumor necrosis factor alpha (10 U/mL), produced a time-dependent decrease in brain capillary TM mRNA (t1/2 of 2.1 and 3.9 hours, respectively) and reduced endothelial TM activity. Incubation of brain capillaries with retinoic acid (10 mumol/L) and dibutyryl cAMP (3 mmol/L) resulted in a 4-fold increase in TM mRNA at 4 and 8 hours, respectively, followed by an increase in protein C activation. We conclude that TM at the blood-brain barrier is likely to be an important physiologic anticoagulant in brain microcirculation. Its downregulation by cytokines may contribute to ischemic brain damage and potentially could be counteracted by retinoic acid and cAMP.
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PMID:Thrombomodulin expression in bovine brain capillaries. Anticoagulant function of the blood-brain barrier, regional differences, and regulatory mechanisms. 940 3

Human Ntera-2 (NT2) cells can be differentiated in vitro into well-characterized populations of NT2N neurons that engraft and mature when transplanted into the adult CNS of rodents and humans. They have shown promise as treatments for neurologic disease, trauma, and ischemic stroke. Although these features suggest that NT2N neurons would be an excellent platform for ex vivo gene therapy in the CNS, stable gene expression has been surprisingly difficult to achieve in these cells. In this report we demonstrate stable, efficient, and nontoxic gene transfer into undifferentiated NT2 cells using a pseudotyped lentiviral vector encoding the human elongation factor 1-alpha promoter and the reporter gene eGFP. Expression of eGFP was maintained when the NT2 cells were differentiated into NT2N neurons after treatment with retinoic acid. When transplanted into the striatum of adult nude mice, transduced NT2N neurons survived, engrafted, and continued to express the reporter gene for long-term time points in vivo. Furthermore, transplantation of NT2N neurons genetically modified to express nerve growth factor significantly attenuated cognitive dysfunction following traumatic brain injury in mice. These results demonstrate that defined populations of genetically modified human NT2N neurons are a practical and effective platform for stable ex vivo gene delivery into the CNS.
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PMID:Genetically modified NT2N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury. 1272 29

The present study investigates the neuroprotective effects of midkine (MK) and retinoic acid (RA) against ischemia in the CNS. Primary cortical neurons, derived from rat E15 embryos (DIV9), were treated with 9-cis-RA (9cRA), all-trans-RA (atRA) or vehicle. Using quantitative PCR, the level of MK mRNA was significantly increased at 4h after 9cRA application. The protective effect of RA and MK was also investigated in adult Sprague-Dawley rats. 9cRA, atRA, MK, or vehicle was injected into the lateral ventricle prior to a 60-min-MCA ligation. Pretreatment with 9cRA or MK attenuated cerebral infarction in stroke animals. Application of a similar dose of atRA did not reduce the size of infarction. In conclusion, our data suggest that 9cRA has neuroprotective effects against ischemia-related brain injury which may involve upregulation of midkine.
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PMID:Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats. 1545 Jun 83

Cell therapy is a rapidly moving field with new cells, cell lines, and tissue-engineered constructs being developed globally. As these novel cells are further developed for transplantation studies, it is important to understand their safety profiles both prior to and posttransplantation in animals and humans. Embryonic carcinoma-derived cells are considered an important alternative to stem cells. The NTera2/D1 teratocarcinoma cell-line (or NT2-N cells) gives rise to neuron-like cells called hNT neurons after exposure to retinoic acid. NT2 cells form tumors upon transplantation into the rodent. However, when the NT2 cells are treated with retinoic acid to produce hNT cells, they terminally differentiate into post-mitotic neurons with no sign of tumorigenicity. Preliminary human transplantation studies in the brain of stroke patients also demonstrated a lack of tumorigenicity of these cells. This review focuses on the use of hNT neurons in cell transplantation for the treatment in central nervous system (CNS) diseases, disorders, or injuries and on the mechanism involved in retinoic acid exposure, final differentiation state, and subsequent tumorigenicity issues that must be considered prior to widespread clinical use.
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PMID:Tumorigenicity issues of embryonic carcinoma-derived stem cells: relevance to surgical trials using NT2 and hNT neural cells. 1572 42

The study tested the hypothesis that transplantation of embryonic stem (ES) cells into rat cortex after a severe focal ischemia would promote structural repair and functional recovery. Overexpression of the human anti-apoptotic gene bcl-2 in ES cells was tested for increasing survival and differentiation of transplanted cells and promoting functional benefits. Mouse ES cells, pretreated with retinoic acid to induce differentiation down neural lineages, were transplanted into the post-infarct brain cavity of adult rats 7 days after 2-h occlusion of the middle cerebral artery (MCA). Over 1-8 weeks after transplantation, the lesion cavity filled with ES cell-derived cells that expressed markers for neurons, astrocytes, oligodendrocytes, and endothelial cells. ES cell-derived neurons exhibited dendrite outgrowth and formed a neuropil. ES cell-transplanted animals exhibited enhanced functional recovery on neurological and behavioral tests, compared to control animals injected with adult mouse cortical cells or vehicle. Furthermore, transplantation with ES cells overexpressing Bcl-2 further increased the survival of transplanted ES cells, neuronal differentiation, and functional outcome. This study supports that ES cell transplantation and gene modification may have values for enhancing recovery after stroke.
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PMID:Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia. 1583 73

All cells, from bacterial to human, have a common, intricate response to stress that protects them from injury. Heat shock proteins (Hsps), also known as stress proteins and molecular chaperones, play a central role in protecting cellular homeostatic processes from environmental and physiologic insult by preserving the structure of normal proteins and repairing or removing damaged ones. An understanding of the interplay between Hsps and cell stress tolerance will provide new tools for treatment and drug design that maximise preservation or restoration of health. For example, the increased vulnerability of tissues to injury in some conditions, such as ageing, diabetes mellitus and menopause, or with the use of certain drugs,, such as some antihypertensive medications, is associated with an impaired Hsp response. Additionally, diseases that are associated with tissue oxidation, free radical formation, disorders of protein folding, or inflammation, may be improved therapeutically by elevated expression of Hsps. The accumulation of Hsps, whether induced physiologically, pharmacologically, genetically, or by direct administration of the proteins, is known to protect the organism from a great variety of pathological conditions, including myocardial infarction, stroke, sepsis, viral infection, trauma, neurodegenerative diseases, retinal damage, congestive heart failure, arthritis, sunburn, colitis, gastric ulcer, diabetic complications and transplanted organ failure. Conversely, lowering Hsps in cancer tissues can amplify the effectiveness of chemo- or radiotherapy. Treatments and agents that induce Hsps include hyperthermia, heavy metals (zinc and tin), salicylates, dexamethasone, cocaine, nicotine, alcohol, alpha-adrenergic agonists, PPAR-gamma agonists, bimoclomol, geldanamycin, geranylgeranylacetone and cyclopentenone prostanoids. Compounds that suppress Hsps include quercetin (a bioflavinoid), 15-deoxyspergualin (an immunosuppressive agent) and retinoic acid. Researchers who are cognisant of the Hsp-related effects of these and other agents will be able to use them to develop new therapeutic paradigms.
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PMID:Heat shock proteins: new keys to the development of cytoprotective therapies. 1599 80

We induced neural cells by treating cynomolgus monkey embryonic stem (ES) cells with retinoic acid. The treated cells mainly expressed betaIIItubulin. They further differentiated into neurons expressing neurofilament middle chain (NFM) in elongated axons. Half of the cells differentiated into Islet1+ motoneurons in vitro. The monkey ES-derived neural cells were transplanted to hemiplegic mice with experimental brain injury mimicking stroke. The neural cells that had grafted into periventricular area of the mice distributed extensively over the injured cortex. Some of the transplanted cells expressed the neural stem/progenitor marker nestin 2 days after transplantation. The cells expressed markers characteristic of mature motoneurons 28 days after transplantation. Mice with the neural cell graft gradually recovered motor function, whereas control animals remained hemiplegic. This is the first demonstration that neural cells derived from nonhuman primate ES cells have the ability to restore motor function in an animal model of brain injury.
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PMID:Transplantation of neural cells derived from retinoic acid-treated cynomolgus monkey embryonic stem cells successfully improved motor function of hemiplegic mice with experimental brain injury. 1613 65

The function of the cerebrospinal fluid (CSF) and the tissue that secretes it, the choroid plexus (CP), has traditionally been thought of as both providing physical protection to the brain through buoyancy and facilitating the removal of brain metabolites through the bulk drainage of CSF. More recent studies suggest, however, that the CP-CSF system plays a much more active role in the development, homeostasis, and repair of the central nervous system (CNS). The highly specialized choroidal tissue synthesizes trophic and angiogenic factors, chemorepellents, and carrier proteins, and is strategically positioned within the ventricular cavities to supply the CNS with these biologically active substances. Through polarized transport systems and receptor-mediated transcytosis across the choroidal epithelium, the CP, a part of the blood-CSF barrier (BCSFB), controls the entry of nutrients, such as amino acids and nucleosides, and peptide hormones, such as leptin and prolactin, from the periphery into the brain. The CP also plays an important role in the clearance of toxins and drugs. During CNS development, CP-derived growth factors, such as members of the transforming growth factor-beta superfamily and retinoic acid, play an important role in controlling the patterning of neuronal differentiation in various brain regions. In the adult CNS, the CP appears to be critically involved in neuronal repair processes and the restoration of the brain microenvironment after traumatic and ischemic brain injury. Furthermore, recent studies suggest that the CP acts as a nursery for neuronal and astrocytic progenitor cells. The advancement of our knowledge of the neuroprotective capabilities of the CP may therefore facilitate the development of novel therapies for ischemic stroke and traumatic brain injury. In the later stages of life, the CP-CSF axis shows a decline in all aspects of its function, including CSF secretion and protein synthesis, which may in themselves increase the risk for development of late-life diseases, such as normal pressure hydrocephalus and Alzheimer's disease. The understanding of the mechanisms that underlie the dysfunction of the CP-CSF system in the elderly may help discover the treatments needed to reverse the negative effects of aging that lead to global CNS failure.
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PMID:The choroid plexus-cerebrospinal fluid system: from development to aging. 1634 1

Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.
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PMID:Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. 1733 85


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