Molecular and cellular mechanisms of neuronal cell death in HIV dementia

Li, W.; Galey, David; Mattson, Mark P.; Nath, Avindra

doi:10.1007/bf03033824

Cited by 77 publications

(63 citation statements)

References 230 publications

(200 reference statements)

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“…Indeed we found synergistic proapoptotic effects when IFN-γ was combined with a challenge of HIV-1 gp120 and Tat proteins ( Figure 1D). Previous investigations have demonstrated cause and effect relationships between production of HIV-1 proteins gp120 and Tat, and neuronal damage [17,19,21]. Consistent with these findings clinical reports detail correlations between HIV-1 proteins, IFN-γ, and neuron cell loss resulting in cognitive decline in HAD patients [14,19,23].…”

Section: Discussionsupporting

confidence: 71%

“…Indeed, pathologic CNS immune dysfunction has been widely explored in many past studies of microglia; the primary host cells for HIV-1 in the CNS [8,13,32,33]. In addition, considering that HIV-1 rarely infects neurons [17], many investigations have focused on neurotoxic effects of viral proteins including HIV-1 gp120 and Tat, acting in concert with proinflammatory circuits mediated by reactive immune cells and soluble factors able to induce or precipitate neuron death in HAD [31].…”

Section: Introductionmentioning

confidence: 99%

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EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-γ: Role of JAK/STAT1 signaling and implications for HIV-associated dementia

et al. 2006

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Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-γ (IFN-γ) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in brains of HIV-1 infected brains progressing to HAD. Recent reports suggest that green tea derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-γ was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-γ enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor or those derived from STAT1-deficient mice were largely resistant to the IFN-γ enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-γ enhanced neurotoxicity of gp120 and Tat, while attenuating JAK/STAT1 pathway activation. EGCG was also found to attenuate the neurotoxic properties of HIV-1 proteins in the presence of IFN-γ in vivo. Taken together, these data suggest that EGCG attenuates the neurotoxicity of IFN-γ augmented neuronal damage from HIV-1 gp120 and Tat both in vitro and in vivo. Thus EGCG ‡

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-γ: Role of JAK/STAT1 signaling and implications for HIV-associated dementia

et al. 2006

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“…With progression of HIV-1, infections patients subsequently can develop HIVE (Gendelman et al, 1994;Li et al, 2005). Previous studies have shown that drugs of abuse such as cocaine enhance the replication of HIV-1 in vitro (Bagasra and Pomerantz, 1993;Gekker et al, 2004;Nair et al, 2005;Peterson et al, 1991;Peterson et al, 1992;Peterson et al, 1993), supporting the hypothesis that drug abuse is a co-factor in the pathogenesis of HIV-1 disease.…”

Section: Discussionmentioning

confidence: 90%

Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA)

et al. 2006

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The US is experiencing an epidemic of cocaine use entangled with HIV-1 infection. Normal human astrocytes (NHA) are susceptible to HIV-1 infection. We utilized LTR-R/U5 amplification, p24 antigen assay and the proteomic method of difference gel electrophoresis (DIGE) combined with protein identification through HPLC-MS/MS to investigate the effect of cocaine on HIV-1 infectivity and the proteomic profile of NHA, respectively. Data demonstrate that cocaine significantly upregulates HIV-1 infection in NHA as measured by LTR-R/U5 amplification and p24 antigen assay. Further, our results show for the first time that cocaine differentially regulates the expression of a number of proteins by NHA that may play a role in the neuropathogenesis of HIV-1 disease.

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“…Neuronal cell death is seen in the brains of patients with HAND. HIV-1 proteins, Tat and gp120 are known to trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations [23,26]. Our data suggests that the neuroprotective properties of paroxetine and fluoxetine are seen at concentrations of 0.5 to10 μM.…”

Section: Discussionmentioning

confidence: 66%

“…HIV-1 proteins, Tat and gp120 trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations [23,26]. We next determined whether SSRIs, paroxetine and fluoxetine, provide neuroprotection against HIV proteins, Tat, gp120 or a combination of Tat and gp120.…”

Section: Neuroprotection By Paroxetine and Fluoxetine Against Neurotomentioning

confidence: 99%

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

et al. 2015

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There are severe neurological complications that arise from HIV infection, ranging from peripheral sensory neuropathy to cognitive decline and dementia for which no specific treatments are available. The HIV proteins secreted from infected macrophages, gp120 and Tat, are neurotoxic. The goal of this study was to screen, identify and develop neuroprotective compounds relevant to HIV-associated neurocognitive disorders (HAND). We screened more than 2000 compounds that included FDA approved drugs for protective efficacy against oxidative stress-mediated neurodegeneration and identified selective serotonin reuptake inhibitors (SSRIs) as potential neuroprotectants. Numerous SSRIs were then extensively evaluated as protectants against neurotoxicity as measured by changes in neuronal cell death, mitochondrial potential, and axodendritic degeneration elicited by HIV Tat and gp120 and other mitochondrial toxins. While many SSRIs demonstrated neuroprotective actions, paroxetine was potently neuroprotective (100 nM potency) against these toxins in vitro and in vivo following systemic administration in a gp120 neurotoxicity model. Interestingly, the inhibition of serotonin reuptake by paroxetine was not required for neuroprotection, since depletion of the serotonin transporter had no effect on its neuroprotective properties. We determined that paroxetine interacts selectively and preferentially with brain mitochondrial proteins and blocks calcium-dependent swelling but had less effect on liver mitochondria. Additionally, paroxetine induced proliferation of neural progenitor cells in vitro and in vivo in gp120 transgenic animals. Therefore, SSRIs such as paroxetine may provide a novel adjunctive neuroprotective and neuroregenerative therapy to treat HIVinfected individuals.

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Molecular and cellular mechanisms of neuronal cell death in HIV dementia

Cited by 77 publications

References 230 publications

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-γ: Role of JAK/STAT1 signaling and implications for HIV-associated dementia

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-γ: Role of JAK/STAT1 signaling and implications for HIV-associated dementia

Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA)

Interaction of Paroxetine with Mitochondrial Proteins Mediates Neuroprotection

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