Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Louboutin, Jean‐Pierre; Strayer, David S.

doi:10.3390/antiox3040770

Cited by 34 publications

(16 citation statements)

References 168 publications

(262 reference statements)

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“…48,49 In our previous studies, we have observed dysregulation of synaptic plasticity genes and decreased spine density in HIV-infected neuronal cells. 6 Therefore, there is a need to investigate the therapeutic molecules that can induce neuroprotection in HIV-infected patients.…”

Section: Discussionmentioning

confidence: 99%

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Atluri¹,

Jayant²,

Pilakka-Kanthikeel³

et al. 2016

IJN

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Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients.

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Section: Discussionmentioning

confidence: 99%

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Atluri¹,

Jayant²,

Pilakka-Kanthikeel³

et al. 2016

IJN

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“…For example, microglia activation was detected in mice that were injected with Tat in the striatum for 7 days (El‐Hage et al, ; Puccini et al, ), and in the brain tissues of a rat model 2 weeks post‐stereotaxical Tat injection in the striatum as well (Agrawal et al, ). Microglia activation upon Tat exposure has been reversed with over‐expression of antioxidant enzymes including Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1), suggesting a role of oxidative stress in Tat‐induced microglia activation (Louboutin et al, ; Louboutin and Strayer, ). An important caveat of the Tat injection models in mice and rats is that the initial injected concentrations of Tat are usually much higher than the physiological levels, although the actual final concentrations of Tat in the animal brains could be significantly lower due to distribution to wider areas as well as Tat degradation in cells and tissues over time (Passiatore et al, ).…”

Section: The Effect Of Viral Proteins On Microglial Functionmentioning

confidence: 99%

Fate of microglia during HIV‐1 infection: From activation to senescence?

Chen

Partridge

Sell

et al. 2016

Glia

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Microglia support productive human immunodeficiency virus type 1 (HIV-1) infection and disturbed microglial function could contribute to the development of HIV-associated neurocognitive disorders (HAND). Better understanding of how HIV-1 infection and viral protein exposure modulate microglial function during the course of infection could lead to the identification of novel therapeutic targets for both the eradication of HIV-1 reservoir and treatment of neurocognitive deficits. This review first describes microglial origins and function in the normal central nervous system (CNS), and the changes that occur during aging. We then critically discuss how HIV-1 infection and exposure to viral proteins such as Tat and gp120 affect various aspects of microglial homeostasis including activation, cellular metabolism and cell cycle regulation, through pathways implicated in cellular stress responses including p38 mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB). We thus propose that the functions of human microglia evolve during both healthy and pathological aging. Aging-associated dysfunction of microglia comprises phenotypes resembling cellular senescence, which could contribute to cognitive impairments observed in various neurodegenerative diseases. In addition, microglia seem to develop characteristics that could be related to cellular senescence post-HIV-1 infection and after exposure to HIV-1 viral proteins. However, despite its potential role as a component of HAND and likely other neurocognitive disorders, microglia senescence has not been well characterized and should be the focus of future studies, which could have high translational relevance.

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“…Envelope glycoprotein-120 is found on the surface of the HIV envelope, where it plays an important role in HIV’s binding to host cells and the subsequent inflammatory response [ 5 ]. It is important to note that brain macrophages and microglia, not neurons are susceptible to HIV-1 infection [ 6 ]. Studies have shown that brain macrophages and microglia infected by HIV-1 ultimately lead to neuronal injury and death [ 1 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of naringin on gp120-induced injury mediated by P2X7 receptors in rat primary cultured microglia

Chen

Jia

et al. 2017

PLoS ONE

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Human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein 120 has been shown to activate microglia, causing release of inflammatory and toxic factors. The P2X7 receptor, primarily expressed on microglia, is closely associated with inflammation. Naringin, a plant bioflavonoid, has anti-inflammatory and anti-oxidative properties. We hypothesized that P2X7 receptor mediated gp120-induced injury in primary cultured microglia, and that naringin would have a protective effect. We showed that HIV-1 gp120 peptide (V3 loop, fragment 308–331) appeared to induce apoptosis of primary cultured microglia. However, there was a decrease of microglia apoptosis in gp120+naringin group compared with gp120 group. Using qPCR, Western blot, and immunofluorescence, we showed that gp120 stimulated expression of P2X7 mRNA and receptor protein, and this stimulation was inhibited by naringin. Treatment with gp120 increased concentrations of eATP, TNFα and IL-1β, and these effects were inhibited by naringin. Taken together, these results suggested that gp120 contributed to microglial cell injury and neurotoxic activity by up-regulating expression of P2X7, in a naringin-protective manner.

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Role of Oxidative Stress in HIV-1-Associated Neurocognitive Disorder and Protection by Gene Delivery of Antioxidant Enzymes

Cited by 34 publications

References 168 publications

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Fate of microglia during HIV‐1 infection: From activation to senescence?

Effect of naringin on gp120-induced injury mediated by P2X7 receptors in rat primary cultured microglia

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