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At least 487 records · Page 27Linked to original sources
PubMed1997

DNA fragmentation in normal development of the human central nervous system: a morphological study during corticogenesis.

Refinement of the cell number by programmed cell death is a major morphogenetic mechanism of the developing central nervous system (CNS) in vertebrates including mammals, which determines to a significant degree its mature cytoarchitecture. We have examined the topography and the extent of cell death in different regions of the human CNS prenatally (11 fetuses), and in the early post-natal weeks (three newborns). Attention was focused on the wall of the telencephalon during a relatively short time period (12th-23rd week of gestation), corresponding to the time of major proliferation in the ventricular zone and to the peak of neuronal migration; both these mechanisms are crucial for corticogenesis. The TUNEL method was used, allowing the recognition of cell death because of its ability to label blunt ends of double-stranded DNA breaks. Morphological features of nuclei at different stages of apoptosis were identified, providing better evidence of the extent of the process than histological stains. Cell labelling was seen in either post-mitotic elements in the ventricular zone, or along the migratory pathways in the intermediate zone and subplate at all prenatal ages examined. No apoptotic nuclei were seen in the cortical plate. These findings suggest that apoptotic cell death drives the selection of cells which are committed to play a role during the early stages of corticogenesis. Lack of evidence of clonally related apoptotic cells also indicates that cell death occurs randomly. Therefore, molecular signals from the surrounding microenvironment seem to be necessary for the apoptotic pathway to be turned on, thus determining the fate of post-mitotic cells.

Aging↗
PubMed2004

Vascular aspects of neuroprotection.

It is being increasingly suggested that the microcirculation, which is known to be in a large part responsible for maintaining an adequate and constant microenvironment for function of the central nervous system, functions as part of a neurovascular unit. The neurovascular unit includes neurons, astrocytes and elements of capillaries. The cerebral circulation exhibits unique functional characteristics and critical elements for the pathogenesis of cerebrovascular disease. For example, the blood-brain barrier formed by epithelial-like high resistance tight junctions within the endothelium is a key feature of microvessels of the central nervous system. Alterations in the microcirculation after ischemia/reperfusion include disruption of the blood-brain barrier, edema and swelling of perivascular astrocyte foot processes, decrease in arteriole endothelium-dependent relaxation and reduced inwardly-rectifying potassium channel function, altered expression of proteases and matrix metalloproteinases, increased inflammatory mediators and inflammation. Experiments studying the microcirculation in ischemia are few compared with those examining neuroprotection, although the two overlap because protection of the microcirculation might achieve some degree of neuroprotection and both processes may be mediated by at least some mechanisms in common.

Animals↗
PubMed2003

Saccadic omnipause and burst neurons in monkey and human are ensheathed by perineuronal nets but differ in their expression of calcium-binding proteins.

The extracellular matrix of the brain contains large aggregates of chondroitin sulfate proteoglycans (CSPG), which form lattice-like cell coatings around distinct neuron populations and are termed perineuronal nets. The function of perineuronal nets is not fully understood, but they are often found around neurons containing the calcium-binding protein parvalbumin, suggesting a function in primarily highly active neurons. In the present paper the distribution of perineuronal nets was studied in two functional cell groups of the primate oculomotor system with well-known firing properties: 1) the saccadic omnipause neurons in the nucleus raphe interpositus (RIP) exhibit a high tonic firing rate, which is only interrupted during saccades; they are inhibitory and use glycine as a transmitter; and 2) premotor burst neurons for vertical saccades in the rostral interstitial nucleus of the medial longitudinal fascicle (RiMLF) fire with high-frequency bursts during saccades; they are excitatory and use glutamate and/or aspartate as a transmitter. In the macaque monkey, both cell populations were identified by their parvalbumin immunoreactivity and were studied for the presence of perineuronal nets using CSPG antibodies or lectin binding with Wisteria floribunda agglutinin. In addition, the expression of another calcium-binding protein, calretinin, was studied in both cell groups. Double- and triple-immunofluorescence methods revealed that both omnipause and burst neurons are selectively ensheathed with strongly labeled perineuronal nets. Calretinin was coexpressed in at least 70% of the saccadic burst neurons, but not in the omnipause neurons. Parallel staining of human tissue revealed strongly labeled perineuronal nets around the saccadic omnipause and burst neurons, in corresponding brainstem regions, which specifically highlighted these neurons within the poorly structured reticular formation. These findings support the hypothesis that perineuronal nets may provide a specialized microenvironment for highly active neurons to maintain their fast-spiking activity and are not related to the transmitter or the postsynaptic action of the ensheathed neurons.

Animals↗
PubMed1994

A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity.

The development and neoplastic progression of human astrocytic tumors appears to result through an accumulation of genetic alterations occurring in a relatively defined order. One such alteration is amplification of the epidermal growth factor receptor (EGFR) gene. This episomal amplification occurs in 40-50% of glioblastomas, which also normally express endogenous receptors. Moreover, a significant fraction of amplified genes are rearranged to specifically eliminate a DNA fragment containing exons 2-7 of the gene, resulting in an in-frame deletion of 801 bp of the coding sequence of the extracellular domain. Here we used retroviral transfer of such a mutant receptor (de 2-7 EGFR) into glioblastoma cells expressing normal endogenous receptors to test whether the mutant receptor was able to augment their growth and malignancy. Western blotting analysis showed that these cells expressed endogenous EGFR of 170 kDa as well as the exogenous de 2-7 EGFR of 140-155 kDa. Although holo-EGFRs were phosphorylated on tyrosine residues only after exposure of the cells to ligand, de 2-7 EGFRs were constitutively phosphorylated. In tissue culture neither addition of EGF nor expression of the mutant EGFR affected the rate of cell growth. However, when cells expressing mutant EGFR were implanted into nude mice subcutaneously or intracerebrally, tumorigenic capacity was greatly enhanced. These results suggest that a tumor-specific alteration of the EGFR plays a significant role in tumor progression perhaps by influencing interactions of tumor cells with their microenvironment in ways not easily assayed in vitro.

Animals↗
PubMed2002

Emergence of muscle and neural hematopoiesis in humans.

During human development, hematopoiesis is thought to be compartmentalized to the fetal circulation, liver, and bone marrow. Here, we show that combinations of cytokines together with bone morphogenetic protein-4 and erythropoietin could induce multiple blood lineages from human skeletal muscle or neural tissue. Under defined serum-free conditions, the growth factors requirements, proliferation, and differentiation capacity of muscle and neural hematopoiesis were distinct to that derived from committed hematopoietic sites and were uniquely restricted to CD45(-)CD34(-) cells expressing the prominin AC133. Our study defines epigenetic factors required for the emergence of hematopoiesis from unexpected tissue origins and illustrates that embyronically specified microenvironments do not limit cell fate in humans.

AC133 Antigen↗
PubMed1984

Selective effects of proteases and phospholipase A2 on monoamine oxidases A and B of human brain and liver.

Human brain and liver mitochondria contain membrane-bound monoamine oxidase of both A and B types. Monamine oxidase-A (MAO-A), either membrane-bound or in detergent-solubilized extracts from these tissues, was selectively inhibited during incubations with trypsin, chymotrypsin, thermolysin, or papain. MAO-A in solubilized, but not in membrane-bound, preparations was also very sensitive to the action of phospholipase A2, while MAO-B was unaffected. Membrane-bound MAO-A of rat brain mitochondria was more sensitive to phospholipases and less sensitive to proteases than was human brain enzyme, indicating that these agents may reveal species differences in MAO properties. Human brain and liver MAO-A, either solubilized or bound in mitochondrial membranes, apparently contains basic and aromatic peptide moieties that are available to proteases. Hydrolysis of these peptide bonds leads to rapid denaturation unless substrate molecules stabilize the active site. Phospholipase A2 may disrupt the phospholipid microenvironment of MAO-A, the integrity of which is essential for MAO-A activity, but not for MAO-B. No interconversion of the two activities was observed. After phospholipase A2 treatment, remaining MAO-A activity was recovered in low-molecular-weight regions of a gel filtration gradient, suggesting that MAO-A subunits were released. Although these experiments argue against the proposal that phospholipids may regulate the ratio of A/B activities of a single enzyme molecule, it is conceivable that endogenous phospholipases or proteases in mitochondrial membranes may influence MAO-A activity independently of MAO-B activity.

Animals↗
PubMed1987

Aluminum-induced conformational changes in calmodulin alter the dynamics of interaction with melittin.

Studies were undertaken to examine the impact of aluminum-induced structural changes in bovine brain calmodulin on the protein's interface region with melittin, a model for calmodulin's target enzymes. Both steady-state and time-dependent fluorescence characteristics of the single tryptophanyl residue of melittin were employed to derive information on aluminum-related changes in the fluorophore's microenvironment. In the presence of stoichiometric amounts of aluminum ions, calmodulin's target region with melittin appears to be more polar than that with aluminum absent. As a result, upon association of melittin with aluminum-calmodulin, the enhancement of helical arrays is less pronounced. The fluorophore's average microenvironment also is modified such that its apparent lifetime is shortened when aluminum is present. In the presence of aluminum ions, the solvation structure of calmodulin is possibly changed, which may be unfavorable for a proper fit between calmodulin and target proteins.

Aluminum↗
PubMed1984

Influence of the beta-adrenergic receptor concentration on functional coupling to the adenylate cyclase system.

Only part of the beta-adrenergic receptors can undergo functional coupling to the adenylate cyclase regulatory unit. This receptor subpopulation shows an increased affinity for agonists in the presence of Mg2+ and undergoes rapid "inactivation" (locking-in of the agonist) by the alkylating reagent N-ethylmaleimide in the presence of agonists. Several experimental conditions, known to modify the total receptor concentration without alteration of the other components of the adenylate cyclase system, do not affect the percentage of receptors that can undergo functional coupling: (i) homologous regulation of beta 1 receptors in rat brain by noradrenaline (through antidepressive drug or reserpine injections); (ii) up- and down-regulation of the beta 2 receptors in Friend erythroleukemia cells by, respectively, sodium butyrate and cinnarizine treatment; and (iii) dithiothreitol-mediated inactivation of receptors in turkey erythrocytes, Friend erythroleukemia cells, and rat brain. Our findings argue against a stoichiometric limitation in the number of regulatory components, genetically different receptor subpopulations, bound guanine nucleotides, or reduced accessibility of part of the receptors to the agonists as the cause for functional receptor heterogeneity. Differences in either the receptor conformation or its membrane microenvironment are more plausible explanations.

Adenylyl Cyclases↗
PubMed1981

Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum.

1. The validity of the macroscopic laws of ion diffusion was critically examined within the microenvironment of the extracellular space in the rat cerebellum using ion-selective micropipettes and ionophoretic point sources. 2. The concepts of volume averaging, volume fraction (alpha) and tortuosity (lambda) were defined and shown to be theoretically appropriate for quantifying diffusion in a complex medium such as the brain. 3. Diffusion studies were made with the cations tetramethylammonium and tetraethylammonium and the anions alpha-naphthalene sulphonate and hexafluoro-arsenate, all of which remained essentially extracellular during the measurements. Diffusion parameters were measured for a period of 50s and over distances of the order of 0.1 mm. 4. Measurements of the diffusion coefficients of the ions in agar gel gave values that were very close to those derivable from the literature, thus confirming the validity of the method. 5. Measurements in the cerebellum did not reveal any systematic influences of ionophoretic current strength, electrode separation, anisotropy, inhomogeneity, charge discrimination or uptake, within the limits tested. 6. The pooled data from measurements with all the ions gave alpha = 0.21 +/- 0.02 (mean +/- S.E. of mean) and lambda = 1.55 +/- 0.05 (mean +/- S.E. of mean). 7. These results show that the extracellular space occupies about 20% of the rat cerebellum and that the diffusion coefficient for small monovalent extracellular ions is reduced by a factor of 2.4 (i.e. lambda 2) without regard to charge sign. The over-all effect of this is to increase the apparent strength of any ionic source in the cerebellum by a factor of lambda 2/alpha, about 12-fold in the present case, and to modify the time course of diffusion. 8. These conclusions confirm that the laws of macroscopic diffusion are closely obeyed in the cerebellum for small ions in the extracellular space, provided that volume fraction and tortuosity are explicitly taken into account. It is likely that these conclusions are generally applicable to other brain regions and other diffusing substances.

Animals↗
PubMed2001

Nitration as a mechanism of Na+, K+-ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus.

Previous studies have shown that hypoxia induces nitric oxide synthase-mediated generation of nitric oxide free radicals leading to peroxynitrite production. The present study tests the hypothesis that hypoxia results in NO-mediated modification of Na+, K+-ATPase in the fetal brain. Studies were conducted in guinea pig fetuses of 58-days gestation. The mothers were exposed to FiO2 of 0.07% for 1 hour. Brain tissue hypoxia in the fetus was confirmed biochemically by decreased ATP and phosphocreatine levels. P2 membrane fractions were prepared from normoxic and hypoxic fetuses and divided into untreated and treated groups. The membranes were treated with 0.5 mM peroxynitrite at pH 7.6. The Na+, K+-ATPase activity was determined at 37 degrees C for five minutes in a medium containing 100 mM NaCl, 20 mM KCl, 6.0 mM MgCl2, 50 mM Tris HCl buffer pH 7.4, 3.0 mM ATP with or without 10 mM ouabain. Ouabain sensitive activity was referred to as Na+, K+-ATPase activity. Following peroxynitrite exposure, the activity of Na+, K+-ATPase in guinea pig brain was reduced by 36% in normoxic membranes and further 29% in hypoxic membranes. Enzyme kinetics was determined at varying concentrations of ATP (0.5 mM-2.0 mM). The results indicate that peroxynitrite treatment alters the affinity of the active site of Na+, K+-ATPase for ATP and decreases the Vmax by 35% in hypoxic membranes. When compared to untreated normoxic membranes Vmax decreases by 35.6% in treated normoxic membranes and further to 52% in treated hypoxic membranes. The data show that peroxynitrite treatment induces modification of Na+, K+-ATPase. The results demonstrate that peroxynitrite decreased activity of Na+, K+-ATPase enzyme by altering the active sites as well as the microenvironment of the enzyme. We propose that nitric oxide synthase-mediated formation of peroxynitrite during hypoxia is a potential mechanism of hypoxia-induced decrease in Na+, K+-ATPase activity.

Animals↗
PubMed1995

Roles of metabotropic glutamate receptors in brain plasticity and pathology.

In summary, the mGluRs are a large family of receptor subtypes with diverse properties in terms of transduction coupling, pharmacology, and anatomical distribution. Many divergent studies have demonstrated that activation of these receptors can result in either neuroprotection or neuropathology. We hypothesized that the mGluRs of astrocytes may have a role in determining the response following administration of mGluR agonists in vivo, and we have defined a suitable in vitro model for the study of these receptors. The experimental plasticity demonstrated in the astrocyte culture model may represent a more general principle that conditions in the microenvironment may differentially alter mGluR subtype expression as part of development, functional specialization, or pathology. This astrocyte model of receptor regulation provides a system suitable for studying the effects of specific growth factors, neurotrophins, cytokines, and other substances released by neurons and glia that may act in both autocrine and paracrine fashions. Alteration in the ratios of receptors by such variables could then modify future signaling properties and neuroglial interactions, a form of conditioning of the astrocytic response that would alter the physiological output following glutamate release. One measure of the value of this model will be its usefulness in stimulating the generation of hypotheses that can be tested in vivo. For example, the morphology of the astrocytes when cultured in the defined medium has similarities to the morphology of astrocytes undergoing reactive gliosis in pathological states. It is also interesting to note that treatments that have been reported to increase excitatory amino acid-stimulated PI hydrolysis in ex vivo brain slices (lesions, ischemia, and kindling) are accompanied by reactive gliosis. Those findings combined with the present in vitro results lead us to speculate that mGluR5 expression may also be altered in vivo during reactive gliosis. If so, it will be important to examine the functional consequences of such a change with regard to the astrocytic response to injury and maintaining the balance between excitatory transmission and excitotoxicity.

Animals↗
PubMed2003

Cytokine immuno-gene therapy for treatment of brain tumors.

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory involving the use of allogeneic cells genetically modified to secrete cytokines. In our studies, mice with an i.c. glioma, melanoma or breast carcinoma treated solely by intratumoral injections with allogeneic cells genetically modified to secrete interleukin-2 (IL-2) were found to survive significantly longer than mice in various control groups. The anti-tumor response was mediated predominantly by T-cell subsets (CD8+ and NK/LAK cells). The injections resulted in the killing of only the neoplastic cells; non-neoplastic cells were unaffected. Experiments involving treatment of animals with i.c. tumor using subcutaneous injections of cytokine-secreting allogeneic cells in the presence of tumor antigens demonstrated no effect in prolonging survival in spite of the development of a vigorous systemic anti-tumor immune response. Of special interest, mice injected intracerebrally with the cytokine-secreting allogeneic cells alone exhibited no neurologic defect and there were no adverse effects on survival. The injection of cytokine-secreting allogeneic cells into the microenvironment of an i.c. tumor is hypothesized to induce an anti-tumor immune response capable of prolonging survival. This pre-clinical animal data directly translates into clinical treatments for patients with a malignant i.c. tumor.

Animals↗
PubMed2005

Cell type-specific regulation of RE-1 silencing transcription factor (REST) target genes.

RE-1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal gene transcription in non-neuronal cells. REST target genes are expressed in neurons and in neuroendocrine cells. Here, we show that treatment with the histone deacetylase inhibitor trichostatin A (TSA) or expression of a mutant of REST (DP-REST:ER) that contains a transcriptional activation domain enhanced expression of the REST target genes encoding synaptophysin and secretogranin II in neuronal as well as in neuroendocrine cells. These data indicate that the synaptophysin and secretogranin II genes are similarly regulated in neuronal and neuroendocrine cells. In contrast, expression of the connexin36 gene was inducible by TSA or DP-REST:ER only in pancreatic alpha and beta cells, but not in neuronal and pituitary cells, indicating that transcriptional repression by REST functions in a cell type-specific manner. Expression of the BDNF and GluR2 genes, both described as targets of REST, was not induced by either TSA or expression of DP-REST:ER in neuronal or neuroendocrine cells. Chromatin immunoprecipitation experiments using antibodies directed against methylated histone H3Lys4 or H3Lys9 showed a perfect correlation between expression of REST target genes in different cell types and nucleosomal modifications that distinguish active from inactive genes. We conclude that the cell type-specific microenvironment, in particular the cell type-specific structure of the chromatin, is crucial for the ability of REST to control gene transcription.

Adrenocorticotropic Hormone↗
PubMed1999

Astrocyte line SVG-TH grafted in a rat model of Parkinson's disease.

The present review describes gene transfer into the brain using extraneuronal cells with an ex vivo approach. The mild immunological reactions in the central nervous system to grafts provided the rationale and empirical basis for brain-transplantation, to replace dying cells, of potential clinical relevance. Fetal human astrocytes were genetically engineered to express tyrosine hydroxylase, the rate-limiting enzyme for the synthesis of catecholamines. These cells were also found to produce constitutively and secrete GDNF and interleukins. Therefore, these cells may prove as a drug-delivery system for the treatment of neurological degenerative conditions such as Parkinson's disease (PD). The field of neuronal reconstruction has reached a critical threshold and there is a need to evaluate the variables that will become critical as the field matures. One of the needs is to characterize the neurochemical alterations in the microenvironment in the context of grafted-host connectivity. This review discusses the functional effects of the pharmacologically-active construct, which consists of astrocytes producing L-DOPA and GDNF. The striatum in PD that lacks the dopaminergic projection from the substantia nigra metabolizes and releases dopamine differently from normal tissue and may react to different factors released by the grafted cells. Moreover, neurochemicals of the host tissue may effect grafted cells as well. An understanding of the way in which these neurochemicals are abnormal in PD and their role in the grafted brain is critical to the improvement of reconstructive strategies using cellular therapeutic strategies.

Animals↗
PubMed2004

Perineuronal nets potentially protect against oxidative stress.

A specialized form of extracellular matrix (ECM) termed perineuronal nets (PNs) consisting of large aggregating chondroitin sulfate proteoglycans (CSPGs), with hyaluronan and tenascin as main components, surrounds subpopulations of neurons. The glycosaminoglycan components of perineuronal nets form highly charged structures in the direct microenvironment of neurons and thus might be involved in local ion homeostasis. The polyanionic character suggests that perineuronal nets also potentially contribute to reduce the local oxidative potential in the neuronal microenvironment by scavenging and binding redox-active iron, thus providing some neuroprotection to net-associated neurons. Here, we show that neurons ensheathed by a perineuronal net in the human cerebral cortex are less frequently affected by lipofuscin accumulation than neurons without a net both in normal-aged brain and Alzheimer's disease (AD). As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalyzed oxidative processes, the present results suggest a neuroprotective function of perineuronal nets against oxidative stress, potentially involved in neurodegeneration.

Aged↗
PubMed2003

Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model.

We employed a genetically defined human cancer model to investigate the contributions of two genes up-regulated in several cancers to phenotypic changes associated with late stages of tumorigenesis. Specifically, tumor cells expressing two structurally unrelated bone-related genes, osteonectin and osteoactivin, acquired a highly invasive phenotype when implanted intracranially in immunocompromised mice. Mimicking a subset of gliomas, tumor cells invaded brain along blood vessels and developed altered vasculature at the brain-tumor interface, suggesting that production of those two proteins by tumor cells may create a complex relationship between invading tumor and vasculature co-opted during tumor invasion. Interestingly, the same tumor cells formed massive spontaneous metastases when implanted subcutaneously. This dramatic alteration in tumor phenotype indicates that cellular microenvironment plays an important role in defining the specific effects of those gene products in tumor behavior. In vitro examination of tumor cells expressing either osteonectin or osteoactivin revealed that there was no impact on cellular growth or death but increased invasiveness and expression of MMP-9 and MMP-3. Specific pharmacologic inhibitors of MMP-2/9 and MMP-3 blocked the increased in vitro invasion associated with osteoactivin expression, but only MMP-3 inhibition altered the invasive in vitro phenotype mediated by osteonectin. Results from this genetically defined model system are supported by similar findings obtained from several established tumor cell lines derived originally from human patients. In sum, these results reveal that the expression of a single bone-related gene can dramatically alter or modify tumor cell behavior and may confer differential growth characteristics in different microenvironments. Genetically defined human cancer models offer useful tools in functional genomics to define the roles of specific genes in late stages of carcinogenesis.

Animals↗
PubMed1997

Recent advances in the biology of central nervous system tumors.

The failure of conventional therapies for many malignant brain tumors has led to a search for more promising alternatives. Recent advances have elucidated a variety of biological factors that act to determine the growth and invasiveness of central nervous system tumors. Such factors include aberrations in the regulation of the cell cycle, apoptosis, and interactions with the host microenvironment. Such insights should translate into novel interventions so that more meaningful outcomes can be achieved in patient care in the future.

Animals↗
PubMed1982

Control of cation transport in cultured glial cells by external Ca++: a possible signal in glial-neuronal interaction.

In cultured glial cells from chick embryonic brain, both influx and efflux of 42K+ and 22Na+ are dependent on the external Ca++ and concentration ([Ca++]0) between 2 and 0.1 mM although intracellular concentrations of K+ ([K+]i) and Na+ ([Na+]i) do not change. Only a reduction of [Ca++]0 below 0.1 mM results in both a decrease of [K+]i and an increase of [Na+]i. Ouabain significantly decreases the [Ca++]0 sensitivity of uphill cation movements (K+ influx and Na+ efflux), while the [Ca++]0 sensitivity of downhill cation movements (K+ efflux and Na+ influx) is almost not affected by the presence of ouabain. Additionally, a decrease in [Ca++]0 triggers an increase in intracellular concentration of adenosine 3':5'-cyclic monophosphoric acid (cAMP). These findings suggest that changes of [Ca++]0, which take place in vivo in the microenvironment of the glia after neuronal firing, represent a signal in the glial-neuronal interaction controlling cation transport and that this control is achieved by a co-operation between the cAMP-generating and the cation transport system.

Animals↗