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At least 955 records · Page 53Linked to original sources
PubMed1986

Cytotoxicity by human adherent cells: oxygen-dependent and -independent cytotoxic reactions by different cell populations.

Human adherent cells, obtained by EDTA reversible adherence to plastic, are potent effectors in cell-mediated cytotoxicity. Spontaneous cytotoxicity in a 2-hr assay against K562 target cells was shown to be largely mediated by contaminating natural killer (NK) cells. Treatment of adherent cells with NK-specific monoclonal antibody anti-Leu-11 plus complement abolished almost completely the spontaneous cytotoxicity. Spontaneous cytotoxicity by adherent cells was also reduced when the phorbol ester PMA was present in the assay. On the other hand, PMA induced a cytotoxic response in NK-cell depleted adherent cells after prolonged 18 hr incubation. The cell population responsible for this dichotomous effect of PMA on adherent cell-mediated cytotoxicity was shown to be monocytes, as revealed by monoclonal antibody treatment. Pure NK cell preparations were not affected by PMA in their cytolytic capacities. Reactive oxygen species are not involved in NK-cell mediated cytotoxicity, while PMA stimulated the monocytes to exert cytolysis and suppressed NK cells by the generation of these highly toxic oxygen products. Hydrogen peroxide especially seemed to be the mediator in this oxygen-dependent monocyte-mediated cytotoxicity and NK-cell suppression.

Catalase↗
PubMed1997

Glutamatergic system and developmental lead neurotoxicity.

The excitatory amino acid receptor subtype N-Methyl-D-Aspartate (NMDA) has been the focus of intense investigation during the last decade because of its role in brain development and synaptic plasticity and in pathological conditions associated with excitotoxicity. This receptor complex has recently been identified to be a target for lead (Pb2+) effects on the developing central nervous system. This presentation is an overview of studies demonstrating the interaction of Pb2+ with the NMDA receptor and its potential effects on cellular function and cognition.

Animals↗
PubMed1992

The T-lymphocyte is the primary cellular target for potentiation of the in vitro T-dependent IgM antibody response by the B subunit of cholera toxin.

The B (or binding) subunit of cholera toxin (CTB) was reported previously to potentiate the in vitro T-dependent IgM antibody response by a mechanism independent of the cyclic AMP-generating capacity of the intact toxin. In the present report, experiments were designed to determine the immune cell type mediating potentiation by CTB. Firstly, CTB did not potentiate T-independent antibody responses at concentrations that effectively enhanced T-dependent responses. Secondly, separation/reconstitution studies with splenocytes from CTB- and vehicle-treated mice demonstrated potentiation of T-dependent responses by CTB treatment of either the Sephadex G10 non-adherent population or the T-lymphocyte + macrophage population of cells. Potentiation was not observed by CTB treatment of the plastic adherent population or the B-lymphocyte + macrophage population. The evidence indicates that the T-lymphocyte is the primary cellular target for CTB-induced effects on the T-dependent IgM antibody response. Monosialoganglioside GM1, the putative binding site for CTB, is most likely the site of action for CTB on T-lymphocytes. These studies provide new insight on the mechanism of immunomodulation by cholera toxin, and CTB should provide a useful tool for further understanding the role of gangliosides in cellular immune responses.

Adjuvants, Immunologic↗
PubMed1996

Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell-cell interactions.

Polysialic acid (PSA), a homopolymer attached to the neural cell adhesion molecule (NCAM), serves as a modulator of cell interactions. Polysialic acid exhibits a highly regulated expression pattern. During embryonic development its abundant expression is closely correlated with axon pathfinding and targeting, and with certain aspects of muscle formation. Its level also can be altered by synaptic activity. During neonatal development and in the adult brain, PSA expression is more restricted, being primarily associated with regions capable of morphological or physiological plasticity. The ability to perturb PSA in vivo by a specific glycosidase and by the creation of NCAM-deficient mice has led to extensive analysis of its biological function. These studies suggest that the primary role of PSA is to promote changes in cell interactions and thereby facilitate plasticity in the structure and function of the nervous system.

Animals↗
PubMed2003

Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.

Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.

Adaptation, Physiological↗
PubMed1998

Establishment of patterned thalamocortical connections does not require nitric oxide synthase.

Subplate neurons are early-generated neurons that project into the overlying neocortex and are required for the formation of ocular dominance columns. A subset of subplate neurons express nitric oxide synthase (NOS) and produce nitric oxide (NO), a neuronal messenger thought to be involved in adult hippocampal synaptic plasticity and also in the establishment of certain specific connections during visual system development. Here, we examine whether the NOS-containing subplate neurons are involved in ocular dominance column formation in the ferret visual system. Ocular dominance columns form in ferrets between postnatal day 35 (P35) and P60. NOS expression in the visual subplate is low at birth, increases to a maximum at the onset of ocular dominance column formation, and falls thereafter. Nevertheless, blockade of NOS with daily injections of nitroarginine from P14 to P56 fails to prevent the formation of ocular dominance columns, although NOS activity is reduced by >98%. To test further a requirement for NOS in the patterning of connections during CNS development, we examined the cortical barrels in the somatosensory system of mice carrying targeted disruptions of NOS that also received injections of nitroarginine; cortical barrels formed normally in these animals. In addition, barrel field plasticity induced by whisker ablation at birth was normal in nitroarginine-injected NOS knock-out mice. Thus, despite the dynamic regulation of NOS in subplate neurons, NO is unlikely to be essential for the patterning of thalamocortical connections either in visual or somatosensory systems.

Aging↗
PubMed2005

Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis.

The matrix metalloproteinase (MMP) enzyme family contributes to the regulation of a variety of brain extracellular matrix molecules. In order to assess their role in synaptic plasticity following traumatic brain injury (TBI), we compared expression of stromelysin-1 (MMP-3) protein and mRNA in two rodent models of TBI exhibiting different levels of recovery: adaptive synaptic plasticity following central fluid percussion injury and maladaptive synaptic plasticity generated by combined TBI and bilateral entorhinal cortical lesion (TBI + BEC). We sampled the hippocampus at 7 days postinjury, targeting a selectively vulnerable brain region and a survival interval exhibiting rapid synaptogenesis. We report elevated expression of hippocampal MMP-3 mRNA and protein after TBI. MMP-3 immunohistochemical staining showed increased protein levels relative to sham-injured controls, primarily localized to cell bodies within the deafferented dendritic laminae. Injury-related differences in MMP-3 protein were also observed. TBI alone elevated MMP-3 immunobinding over the stratum lacunosum moleculare (SLM), inner molecular layer and hilus, while TBI + BEC generated more robust increases in MMP-3 reactivity within the deafferented SLM and dentate molecular layer (DML). Double labeling with GFAP confirmed the presence of MMP-3 within reactive astrocytes induced by each injury model. Semi-quantitative RT-PCR revealed that MMP-3 mRNA also increased after each injury, however, the combined insult induced a much greater elevation than fluid percussion alone: 1.9-fold vs. 79%, respectively. In the TBI + BEC model, MMP-3 up-regulation was spatio-temporally correlated with increased enzyme activity, an effect which was attenuated with the neuroprotective compound MK-801. These results show that distinct pathological conditions elicited by TBI can differentially affect MMP-3 expression during reactive synaptic plasticity. Notably, these effects are both transcriptional and translational and are correlated with functionally active enzyme.

Animals↗
PubMed2002

Long-term depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1.

Protein kinase cascades likely play a critical role in the signaling events that underlie synaptic plasticity and memory. The extracellular signal-regulated kinase (ERK) cascade is suited well for such a role because its targets include regulators of gene expression. Here we report that the ERK cascade is recruited during long-term depression (LTD) of synaptic strength in area CA1 of the adult hippocampus in vivo and selectively impacts on phosphorylation of the nuclear transcription factor Elk-1. Using a combination of in vivo electrophysiology, biochemistry, pharmacology, and immunohistochemistry, we found the following: (1) ERK phosphorylation, including phosphorylation of nuclear ERK, and ERK phosphotransferase activity are increased markedly, albeit transiently, after the induction of NMDA receptor-dependent LTD at the commissural input to area CA1 pyramidal cells in the hippocampus of anesthetized adult rats; (2) LTD-inducing paired-pulse stimulation fails to produce lasting LTD in the presence of the ERK kinase inhibitor SL327, which suggests that ERK activation is necessary for the persistence of LTD; and (3) ERK activation during LTD results in increased phosphorylation of Elk-1 but not of the transcription factor cAMP response element-binding protein. Our findings indicate that the ERK cascade transduces signals from the synapse to the nucleus during LTD in hippocampal area CA1 in vivo, as it does during long-term potentiation in area CA1, but that the pattern of coupling of the ERK cascade to transcriptional regulators differs between the two forms of synaptic plasticity.

Animals↗
PubMed2002

Ageing and diabetes: implications for brain function.

Diabetes mellitus is associated with moderate cognitive deficits and neurophysiological and structural changes in the brain, a condition that may be referred to as diabetic encephalopathy. Diabetes increases the risk of dementia, particularly in the elderly. The emerging view is that the diabetic brain features many symptoms that are best described as "accelerated brain ageing." The clinical characteristics of diabetic encephalopathy are discussed, as well as behavioural (e.g. spatial learning) and neurophysiological (e.g. hippocampal synaptic plasticity) findings in animal models. Animal models can make a substantial contribution to our understanding of the pathogenesis, which shares many features with the mechanisms underlying brain ageing. By unravelling the pathogenesis, targets for pharmacotherapy can be identified. This may allow treatment or prevention of this diabetic complication in the future. We discuss changes in glutamate receptor subtypes, in second-messenger systems and in protein kinases that may account for the alterations in synaptic plasticity. In addition, the possible role of cerebrovascular changes, oxidative stress, nonenzymatic protein glycation, insulin and alterations in neuronal calcium homeostasis are addressed.

Aging↗
PubMed1979

Depletion of NK by cellular immunoadsorption.

The binding of human natural killer (NK) cells to their tumor cell targets was investigated by using monolayers of sensitive target cell lines. Monolayers of K562 and HSB, a myeloid and T cell line, respectively, were prepared on poly-L-lysine-coated plastic tissue culture dishes and briefly fixed with 0.2% formaldehyde. Freshly isolated peripheral blood lymphocytes (PBL) were incubated on the monolayers. Nonadherent PBL were then removed, after gentle agitation, by decanting and gently washing the monolayer. They were tested, along with unseparated controls, for NK activity in a short-term 51Cr release assay. PBL that were nonadherent to a tested monolayer had only 20 to 60% of the control cytotoxic activity. Our results suggest that NK recognition sites on the effector lymphocytes were able to interact with reciprocal determinants on the target cell monolayers, resulting in selective loss of NK effector cells from the PBL population. The specificity of the NK effector-target interaction was investigated by testing the ability of each monolayer to remove activity against both targets. These data imply heterogeneity with regard to recognition structure within the NK effector population as well as among the target cells.

Adult↗
PubMedDate not supplied

[Glutathione in cognitive function and neurodegeneration].

OBJECTIVE: To review the main findings on the glutathione role in cognitive function and synaptic plasticity processes, as well as, its involvement in neurotrophic and neurodegenerative events in rodents. DEVELOPMENT: The tripeptide glutathione and its related enzymes participate in the maintenance of oxidant homeostasis in aerobic cells. Oxidative damage to neuronal components underlies the molecular basis of neurodegeneration and brain aging. Several biomolecules with redox dependent activity are involved in the neuronal plasticity events that have a role in learning and memory functions. The maintenance of normal glutathione level is important for acquisition, but not consolidation, of spatial memory. Glutathione unavailability induces failures in hippocampal synaptic plasticity mechanisms, which are possibly related to a spatial memory deficit. On the other hand, several studies have suggested that the beneficial effects of neurotrophic treatments are mediated by the modulation of antioxidant defense mechanisms. In fact, nerve growth factor treatment to cognitively impaired rats stimulates glutathione reductase and can prevent the increases in glutathione peroxidase activity, pointing these enzymes as possible intracellular targets of neurotrophin actions on oxidant homeostasis. CONCLUSION: There is a closed link between glutathione metabolism and oxidant homeostasis, which is expressed in learning and synaptic plasticity deficits in conditions of low glutathione content, as well as, in neurodegeneration induced glutathione metabolism changes that can be prevented by neurotrophic treatment

Aging↗
PubMed2003

GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability.

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD67 and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix. Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD67 promoter CpG islands, which downregulates their expression. In addition, we report preliminary evidence suggesting that by targeting this chromatin-remodeling deficit with inhibitors of histone deacetylases (HDAC), it may be possible to reduce the DNMT upregulation via a covalent modification of nucleosomal histone tails, underscoring the possibility that by addressing a chromatin remodeling deficit, one may treat psychiatric disorders.

Animals↗
PubMed2004

Apolipoprotein E4 as a target for developing new therapeutics for Alzheimer's disease.

The identification of factors that influence the onset or progression of the sporadic form of Alzheimer's disease (AD) is a key step toward understanding its mechanism(s) and developing successful rational therapies. The apoE genotype has been identified as a powerful risk factor for AD that may account for as much as 50% of the sporadic form of the disease. As the major risk factor for late-onset AD, apolipoprotein E4 (apoE4) should be considered a good target for AD drug discovery. However, despite knowing for over a decade that apoE4 is detrimental to the disease process, we still remain uncertain about the molecular mechanisms subserving the risk-factor activity of apoE4. This, coupled with the fact that we know relatively little about the function(s) of apoE in brain, has presented a barrier to developing apoE-based therapeutics for AD. Progress has been made in understanding the neurobiology of apoE; a number of potentially overlapping functions have been ascribed, which include lipid transport, neuronal repair, dendritic growth, maintenance of synaptic plasticity, and anti-inflammatory activities. Until the gaps are filled in our understanding of the pathogenic function(s) of apoE4, therapeutic strategies targeting this protein will lag behind the development of other AD therapies. Putative pathological functions, or risk-factor activities, of apoE4 include its role in beta-amyloid deposition, neurofibrillary tangle formation, synaptic loss, lipid dysfunction, neuroinflammation, and oxidative stress.

Alzheimer Disease↗
PubMed2004

[Glutamatergic neurotransmission as molecular target in anxiety].

Glutamate (GLU) is the main excitatory neurotransmitter in the mammalian brain. GLU receptors are classified as ionotropic (iGLUR) or metabotropic (mGLUR). The GLU interference with neural development, synaptic plasticity, learning and memory, epilepsy, neural ischemia, drug addiction, tolerance, neuropathic pain, anxiety and depression, has limited the use of compounds acting on GLU synapses, when there is a need for a selective effect for these drugs. Pre-clinical data in rodents and humans subjects has shown that compounds that reduce GLU activation either by blocking its receptors or by reducing its release from terminals elicit an anxiolytic profile of action in models of anxiety. When applied to specific brain areas involved in the mediation of defensive behavior, such as the periaqueductal gray matter, these compounds also replicate the same anxiolytic-like profile. The increasing knowledge about GLU neurotransmission and the development of more selective GLU-acting compounds have renewed attention towards this neurotransmismiting system as a possible target for new classes of drugs for the treatment of neuropsychiatric conditions. Although not complete this review tried to draw attention to collaborative studies between clinicians and basic researchers that have provided insight for potential targets in the development of new anxiolytic compounds thus contributing for the understanding of the biological basis of anxiety.

Animals↗
PubMed2006

Alcohol potently modulates climbing fiber-->Purkinje neuron synapses: role of metabotropic glutamate receptors.

Consumption of alcoholic beverages produces alterations in motor coordination and equilibrium that are responsible for millions of accidental deaths. Studies indicate that ethanol produces these alterations by affecting the cerebellum, a brain region involved in the control of motor systems. Purkinje neurons of the cerebellar cortex have been shown to be particularly important targets of ethanol. However, its mechanism of action at these neurons is poorly understood. We hypothesized that ethanol could modulate Purkinje neuron function by altering the excitatory input provided by the climbing fiber from the inferior olive, which evokes a powerful all-or-none response denoted as the complex spike. To test this hypothesis, we performed whole-cell patch-clamp electrophysiological and Ca2+ imaging experiments in acute slices from rat cerebella. We found that ethanol potently inhibits the late phase of the complex spike and that this effect is the result of inhibition of type-1 metabotropic glutamate receptor-dependent responses at the postsynaptic level. Moreover, ethanol inhibited climbing fiber long-term depression, a form of synaptic plasticity that also depends on activation of these metabotropic receptors. Our findings identify the climbing fiber-->Purkinje neuron synapse as an important target of ethanol in the cerebellar cortex and indicate that ethanol significantly affects cerebellar circuits even at concentrations as low as 10 mm (legal blood alcohol level in the United States is below 0.08 g/dl = 17 mm).

Alanine↗
PubMed1994

T cells are the cellular target of the proliferation-augmenting effect of chronic low-dose ionizing radiation in mice.

The proliferative response to mitogenic stimulation by splenocytes can be augmented by exposing mice to whole-body, chronic, intermittent low doses of ionizing radiation, referred to here as low-dose irradiation. The purpose of this study was to identify the cell(s) in the spleen which is responsive to the proliferation-augmenting effect of low-dose irradiation, i.e., the cellular target. C57BL/6 mice were subjected to low-dose irradiation (0.04 Gy/exposure/day, 5 consecutive days/week, 2 weeks) or to sham irradiation. Three days after the last exposure, spleens were removed, separated into cell fractions which were nonadherent and adherent to plastic surfaces and reconstituted in various combinations, and their proliferative responses to various mitogens were determined. Highly purified T cells were also used in place of the nonadherent cell fraction in the reconstitution studies. The target cells were shown to be T cells. The target T cells of low-dose-irradiated mice possessed elevated constitutive levels of HSP-70 mRNA and HSP-72, and they responded to T-cell receptor-specific anti-CD3 stimulation by producing more HSP-70 mRNA and HSP-72 and by proliferating more extensively than T cells of sham-irradiated mice.

Animals↗
PubMed2003

A conditioned stressful environment causes short-term metaplastic-like changes in the rat nucleus accumbens.

Stress-related alterations to the induction of hippocampal synaptic plasticity have been implicated in certain forms of psychiatric disorders. However, relatively little is known about such changes in other psychiatric disorders-related structures. We tested this possibility in one of such structures, the nucleus accumbens, during re-exposure of rats to a conditioned stressful environment, in which they had previously received shock. In both control rats (no shock) and shocked rats previously submitted to an extensive pre-exposure to the to-be-conditioned contextual cues (latent inhibition), high- and low-frequency stimulation of fimbria-accumbens pathway induced, in the nucleus accumbens, similar pattern of increases and decreases in synaptic efficacy, respectively. However, in non-pre-exposed shocked rats, re-exposure to the conditioned contextual cues evoked high levels of freezing, which was accompanied by a blockade of the induction of enhancement, but a facilitation of the depression, of synaptic efficacy. In addition, contextual conditioning did not alter the baseline transmission whatever the stimulus intensity and was ineffective on the induction of fimbria-accumbens synaptic plasticity following complete extinction of freezing response to the conditioned contextual cues. These data support the idea according to which stress may be involved in certain forms of psychiatric disorders via induction of metaplastic changes in circuits including the hippocampus and hippocampal limbic target structures such as the nucleus accumbens.

Animals↗
PubMed1991

Plasticity of spinal systems after unilateral lumbosacral dorsal rhizotomy in the adult rat.

Plasticity of spinal systems in response to lumbosacral deafferentation has previously been described for the cat, by using immunocytochemistry to demonstrate plasticity of tachykinin systems and degeneration methods to demonstrate plasticity of descending systems. In this study, we describe the response to lumbosacral deafferentation in the adult rat. Application of immunocytochemical methods to visualize tachykinins (predominantly substance P magnitude of SP), serotonin (5-HT), and dopamine B-hydroxylase (DBH), the synthesizing enzyme for norepinephrine, permits us to compare the response of SP systems in rat and cat spinal cord and to examine the response of two descending systems, serotoninergic and noradrenergic, to deafferentation. We used image analysis of light microscopic preparations to quantify the immunoreaction product in the spinal cord in order to estimate the magnitude, time course and localization of changes induced by the lesion. The distribution of SP, serotoninergic (5-HT), and noradrenergic staining in the spinal cord of rat is very similar to that of the cat. Unilateral lumbosacral rhizotomy elicits a partial depletion, followed by a partial replacement of tachykinin immunoreactivity in laminae I and II. This response was similar to that described for the cat, although characterized by a longer time course, and, as in the cat, is likely due to plasticity of tachykinin containing interneurons. The same lesion elicits no depletion but a marked and permanent increase in 5-HT immunoreactivity in laminae I and II, which develops more rapidly than the response by the SP system. These results indicate sprouting or increased production of SP and 5-HT in response to deafferentation. No change was seen in DBH immunoreactivity, indicating that the noradrenergic system does not show plasticity in response to deafferentation. Our results demonstrate that dorsal rhizotomy evokes different effects in different systems in the adult spinal cord of the rat and thus suggests that the response of undamaged pathways to partial denervation of their target is regulated rather than random.

Afferent Pathways↗