Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: CAS:6893-26-1 (glutamate)
73,096 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

The human immunodeficiency virus type 1 coat protein, gp120, kills neurons in primary cortical cultures at low picomolar concentrations. The toxicity requires external glutamate and calcium and is blocked by glutamate receptor antagonists. Nitric oxide (NO) contributes to gp120 toxicity, since nitroarginine, an inhibitor of NO synthase, prevents toxicity as does deletion of arginine from the incubation medium and hemoglobin, which binds NO. Superoxide dismutase also attenuates toxicity, implying a role for superoxide anions.
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PMID:Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. 809 16

The pathogenesis of the human immunodeficiency virus (HIV)-associated cognitive/motor complex, or acquired immunodeficiency syndrome (AIDS) dementia complex, is unknown, but it afflicts over 50% of all patients infected with HIV-1. Because neurons are not directly infected with HIV-1, the causes of neuronal dysfunction are undoubtedly indirect. We investigated the role of the astrocyte in the development of AIDS dementia complex, focusing on cytokine and HIV-1 gp120 stimulation of Na+/H+ exchange (NHE) activity of primary rat astrocytes. Our results show that the cytokines tumor necrosis factor-alpha, interferon (IFN)-gamma, and interleukin (IL)-1 beta (all found to be elevated in the central nervous system of AIDS patients), can stimulate Na+/H+ exchange, but that transforming growth factor-beta, IL-2, and IL-6 do not. IFN-gamma and gp120-induced activation of Na+/H+ exchange appears to be mediated through activation of tyrosine kinase (TK), because TK inhibitors block the action of IFN-gamma and gp120. Additionally, gp120 induces tyrosine phosphorylation of two proteins (approximately 90 and 130 kDa), which is also inhibited by TK inhibitors. The predominant NHE isoform present in rat astrocytes is NHE-1; however, other isoforms are also present. We conclude that Na+/H+ exchange of rat astrocytes can be differentially stimulated by cytokines and HIV-1 gp120. We hypothesize that the resultant increase in intracellular pH with its concomitant changes in astrocyte membrane permeability properties produces an imbalance in the K+ and glutamate microenvironment of the neurons, leading to a rise in intraneuronal Ca2+ and eventual neuronal dysfunction and/or demise.
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PMID:Cytokines and HIV envelope glycoprotein gp120 stimulate Na+/H+ exchange in astrocytes. 818 58

Infection by human immunodeficiency virus type 1 (HIV-1) is often complicated by a variety of neurological abnormalities. The most common clinical syndrome, termed acquired immunodeficiency syndrome (AIDS) dementia complex, presents as a subcortical dementia with cognitive, motor, and behavioral disturbances and is unique to HIV-1 infection. The pathogenesis of this syndrome is poorly understood but is believed to involve interactions among virally infected macrophages/microglia, astrocytes, and neurons. In this study, we show that exposure of primary rat and human astrocytes to heat-activated HIV-1 virions, or to eukaryotically expressed HIV-1 and HIV-2 envelope glycoproteins (gp120) stimulates amiloride-sensitive Na+/H+ antiport, potassium conductance, and glutamate efflux. These effects are blocked specifically by amiloride, an inhibitor of Na+/H+ antiport and by the selective removal of gp120 with immobilized monoclonal antibody. As a result of modulation of astrocytic function by gp120, the ensuing neuronal depolarization and glutamate exposure could activate both voltage-gated and N-methyl-D-aspartate-regulated Ca2+ channels, leading to increases in intraneuronal Ca2+ and neuronal death. These findings implicate the astrocyte directly in the pathogenesis of AIDS dementia complex.
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PMID:Envelope glycoprotein gp120 of human immunodeficiency virus type 1 alters ion transport in astrocytes: implications for AIDS dementia complex. 829 May 53

Exposure of rat cortical neurons to the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 in vitro causes a rise in the intracellular Ca2+ level and a subsequent translocation of protein kinase C (PKC) from the cytosol to the membrane. Such a translocation persists for at least 2 h, but only in cultures with media not depleted of endogenous glutamate. Enzymatic degradation of glutamate in the medium by the enzyme glutamate-pyruvate transaminase (GPT) abolishes the long-lasting effect of gp120 on the association state of PKC; under this incubation condition the translocation period is < 1 h. Memantine and the ganglioside GM1 prevent N-methyl D-aspartate receptor-mediated long-term translocation of PKC and gp120-mediated neurotoxicity (in the absence of GPT); they have no effect on short-term translocation of PKC. We suggest that gp120-caused neuronal death involves an indirect sensitization step of the NMDA receptors, which ultimately induces neuronal death.
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PMID:HIV-1 gp120 and NMDA induce protein kinase C translocation differentially in rat primary neuronal cultures. 845 39

Infection by lentiviruses such as human immunodeficiency virus (HIV) and Maedi-Visna virus (MVV) is associated with neurodegenerative disorders. We have investigated the neurotoxic mechanisms of a synthetic peptide of transactivating protein tat of MVV in striatal neuronal cultures. Tat peptide (but not control peptide) caused neuronal death, without affecting glial viability, in a time- and dose-dependent manner. Significant neuronal death was not observed until 6-8 h after tat peptide application (2.35-2350 nM), whereas half maximal and maximal cell death was observed after 12 and 24 h respectively. Tat peptide neurotoxicity could be partially inhibited by blockade of either N-methyl-D-aspartate (NMDA)- or non-NMDA receptors, suggesting that excessive neuroexcitation by glutamate or its analogues may contribute to tat-neurotoxicity. Furthermore, when both these glutamate receptor subtypes were blocked simultaneously, an increased degree of neuroprotection was observed. Finally, tat peptide toxicity was also reduced by blockade of L-type calcium channels. Calcium imaging revealed that intracellular calcium increases slowly upon tat application, predominantly due to entry of extracellular calcium. These results indicate that cellular calcium entry through voltage-gated calcium channels following activation of both NMDA and non-NMDA receptors, and subsequent accumulation of intracellular calcium may contribute to the neuronal death induced by tat protein.
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PMID:Neurotoxic mechanisms of transactivating protein Tat of Maedi-Visna virus. 855 2

Human immunodeficiency virus (HIV) infection is commonly associated with neurological disease that occurs in the apparent absence of extensive infection of brain cells by HIV, suggesting that indirect mechanisms account for neuropathogenesis in the CNS, perhaps including changes in the normal neuroprotective functions of astrocytes. To test this hypothesis, we examined the effect of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha), produced by HIV-1-infected macrophages and microglia, on glutamate transport by primary human fetal astrocytes (PHFAs). A dose-dependent inhibition of high affinity glutamate uptake sites was observed 12-24 h after addition of exogenous recombinant human TNFalpha to PHFAs. This effect was specific since it was blocked by a neutralizing monoclonal antibody directed against TNFalpha. Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that is an agonist at the 55-kDa TNF receptor. These results suggest that the neurotoxic effects of TNFalpha may be due in part to its ability to inhibit glutamate uptake by astrocytes, which in turn may result in excitotoxic concentrations of glutamate in synapses.
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PMID:Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia. 866 35

Selection of the IIIB strain of human immunodeficiency virus type (HIV-1) resistant to the (alkylamino)piperidine-bis(heteroaryl)piperazine (AAP-BHAP) U-104489 results in substitution of a glycine to glutamate at residue 190 (G190E) of reverse transcriptase (RT). The AAP-BHAP resistant HIV-1 displays reduced in vitro replication capacity [Olmsted, R. A., et. al. (1966) J. Virol. 70, 3698-3705]. We report here that the G190E mutation in recombinant heterodimeric HIV-1 RT, compared to the wild-type RT (G190) or a G190A control mutant, results in a 40% and 80% reduction in the polymerase and RNase H specific enzymatic activities, respectively. A primer-extension assay that allowed determination of DNA elongation by the G190E mutant RT on a heteropolymeric HIV-1 gag-based RNA template showed an overall decrease in DNA polymerization. The size distribution of products generated by G190E RT-associated RNase H digestion of RNA from [35S]poly(rA).poly(dT) was markedly distinct from that of the G190A RT and was consistent with the observed reduction in RT-associated RNase H activity of the G190E RT. When challenged with unlabeled substrates, the G190E RT was relatively nonprocessive with respect to DNA synthesis and RNA degradation. It is concluded that the deleterious effect of the G190E resistance mutation on both of these RT functions is most likely involved in the observed retarded replication capacity of the AAP-BHAP-(U-104489-) resistant HIV-1.
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PMID:A drug resistance mutation in the inhibitor binding pocket of human immunodeficiency virus type 1 reverse transcriptase impairs DNA synthesis and RNA degradation. 870 45

The human immunodeficiency virus coat protein gp120 injures central mammalian neurons both in vitro and in vivo, and this observation may contribute, at least in part, to the neurological dysfunction associated with the acquired immunodeficiency syndrome. Recent work suggests that gp120 mediates neuronal damage predominantly via an indirect route involving activation of brain macrophages. We have previously shown that the stimulation of N-methyl-D-aspartate receptors by excitatory amino acids is essential for the neuronal injury observed with gp120. Here we show that gp120 impairs astrocyte uptake of excitatory amino acids and the excess glutamate thus engendered may contribute to the increased neuronal damage. We also studied the mechanism whereby gp120 inhibits the uptake of excitatory amino acids by astrocytes. We present data suggesting that at least one pathway involves a direct effect of gp120 on macrophages, which in turn release arachidonic acid, a known inhibitor of excitatory amino acid uptake by astrocytes. Our findings suggest that the observed effects on glia and neurons of gp120 may be secondary, at least in part, to its initial activation of macrophages.
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PMID:The coat protein gp120 of HIV-1 inhibits astrocyte uptake of excitatory amino acids via macrophage arachidonic acid. 884 55

A significant number of people infected with the human immunodeficiency virus (HIV) develop neurologic complications. The AIDS dementia complex is frequently accompanied by HIV encephalitis, which is characterized at the neuropathologic level by loss of neuronal subpopulations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage, astrogliosis, and formation of microglial nodules and multinucleated giant cells. Recent studies have shown that the extent of neurodegeneration in this condition correlates directly with the amount of HIV-1 antigen in the brain. HIV-1 infection of the brain could result in neurodegeneration via neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or via alterations in the expression of host factors. The latter may include increased production of potentially detrimental factors such as cytokines, excitotoxic amino acids, free oxygen radicals, and bioactive lipid mediators as well as interference with the production or action of neurotrophic/protective factors. Derangements of the neuronal calcium homeostasis, lipid peroxidation, and induction of programmed cell death (apoptosis) may all play a role as final common pathogenetic pathways in HIV-1-induced neurodegeneration. Recent studies in transgenic mice (over)expressing HIV- or host-derived proteins in their central nervous system indicate that distinct neuronal populations may differ in their susceptibility to specific pathogenic factors. For example, glutamate-receptor-bearing pyramidal neurons were particularly susceptible to neurodegeneration promoted by HIV-1 products, whereas interneurons were more sensitive to the neurotoxic effects mediated by cytokines. For the design of effective treatments for the HIV-1-associated cognitive/motor complex, it will be important to determine whether the neurologic deficits in this entity result from global neuronal dysfunction or relate more specifically to the impairment of distinct neuronal subpopulations. It will also be critical to examine diverse in vitro and in vivo models to help decide which of the many pathogenetic processes that may be at work in this complex disease constitute the most promising therapeutic targets.
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PMID:Pathogenesis of HIV-1 associated neurodegeneration. 885 54


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