Increased glutamate in CSF and plasma of patients with HIV dementia

Ferrarese, Carlo; Aliprandi, Angelo; Tremolizzo, Lucio; Stanzani, Lorenzo; Micheli, A; Dolara, Alberto; Frattola, L.

doi:10.1212/wnl.57.4.671

Cited by 157 publications

(108 citation statements)

References 26 publications

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“…18,19 In this context, HIV-1 Vpr mediates many processes that facilitate HIV-1 infection and promote persistence in the host cells. 3,13 Our earlier studies using SILAC-based proteomics analysis demonstrated that numerous enzymes in the glycolytic pathway and TCA cycle were altered in response to HIV-1 Vpr in macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…16 HAD has been linked to macrophage toxin production including glutamate. [17][18][19][20] Increased glutamate levels are also seen in the plasma, and cerebrospinal fluid (CSF) of HIV-1 infected patients. 18,21 In addition, the observation that soluble Vpr is detected in the CSF of HIV-1 infected individuals 22 suggests that Vpr can have bystander effects on uninfected cells and on neuronal cells 23 and contribute to glutamate-mediated neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

et al. 2016

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HIV-1 infected macrophages play a significant role in the neuropathogenesis of AIDS. HIV-1 viral protein R (Vpr) not only facilitates HIV-1 infection but also contribute to long-lived persistence in macrophages. Our previous studies using SILAC-based proteomic analysis showed that the expression of critical metabolic enzymes in the glycolytic pathway and tricarboxylic acid (TCA) cycle were altered in response to Vpr expression in macrophages. We hypothesized that Vpr-induced modulation of glycolysis and TCA cycle regulates glutamate metabolism and release in HIV-1 infected macrophages.We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of a-ketoglutarate (a-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, a-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

et al. 2016

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“…Since high levels of glutamate inhibit the proliferation of T-cells, glutamate has been related to immune deficiency (Ferrarese et al, 2001). Most attention has been focused on mGluR expression in thymocytes and T lymphocytes.…”

Section: Immune System and Thymusmentioning

confidence: 99%

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

Durand¹,

Carniglia²,

Caruso³

et al. 2011

Anxiety Disorders

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“…Increased Glu has been found in CSF of acute MS patients (154) and secondary progressive MS (155). Excess glutamate has also been found in HAD patient populations (156). Increases in extracellular glutamate are known to occur through a variety of mechanisms including reversal of glutamate uptake carriers, impairment of membrane integrity, swellinginduced opening of anion channels, compromise of the blood brain barrier and enzymatic conversion of glutamine to glutamate (157).…”

Section: Excess Generation Of Extracellular Glutamate In Hadmentioning

confidence: 99%

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

Erdmann¹,

Whitney²,

Zheng³

2006

Clinical Neuroscience Research

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HIV-1 Associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis.

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Increased glutamate in CSF and plasma of patients with HIV dementia

Abstract: Increased CSF glutamate may originate within the CNS and may play a pathogenetic role in HIV dementia, thus supporting the treatment of these patients with glutamate receptor antagonists.

Cited by 157 publications

References 26 publications

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

Glutamate metabolism in HIV-1 infected macrophages: Role of HIV-1 Vpr

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

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