Cell death in HIV dementia

Mattson, Mark P.; Haughey, Norman J.; Nath, Avindra

doi:10.1038/sj.cdd.4401577

Cited by 261 publications

(251 citation statements)

References 169 publications

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“…Clearly viral proteins can bind to cell surface receptors such as CXCR4 and N-methyl-D-aspartate receptors. Thus HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity resulting from altered cellular intracellular calcium concentrations and mitochondrial dysfunction [19]. Inflammation and proinflammatory soluble factors also play important roles in the pathogenesis and progression of HAD.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…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%

“…Because neuronal cell death by oxidative and excitotoxic stress is seen in the brains of patients with HAND [23,24], we used 3-NP-, H 2 O 2 -and NMDA -induced neurotoxicity in an in vitro model to test neuroprotective effect of SSRIs. Initially, we screened the Microsource Spectrum collection for neuroprotectants against the oxidative stresser 3-NP (see [25].…”

Section: Neuroprotection By Paroxetine and Fluoxetine Against Neurotomentioning

confidence: 99%

“…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%

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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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“…The incidence of the socalled HIV-1-associated dementia (HAD) is increasing, and its pathogenesis is likely to be complex, involving multiple direct and indirect apoptosis-inducing mechanisms culminating in neurodegeneration. [11][12][13] Soluble viral products such as gp120 and Tat as well as inflammatory responses play a major role in HAD. 12 Moreover, direct mechanisms leading to the formation of synctia may contribute to HAD.…”

mentioning

confidence: 99%