Neurotoxicity of HIV coat protein gp120, NMDA receptors, and protein kinase C: A study with rat cerebellar granule cell cultures

Savio, Tiziana; Levi, Giulio

doi:10.1002/jnr.490340303

Cited by 112 publications

(64 citation statements)

References 20 publications

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“…Furthermore, preliminary experiments indicate that both SDF-1μ and PD0183812 reduce the overexpression of cyclin D1 caused by potassium deprivation. In contrast, the HIV envelope protein gp120 IIIB did not inhibit K5-induced apoptosis ( Figure 7A) and Rb phosphorylation ( Figure 7B)-but rather increased Rb phosphorylation in normal conditions, i.e., K25 mM ( Figure 7B, bottom), in agreement with previous evidence reporting gp120 neurotoxicity in these cultures (Savio and Levi, 1993). The viral protein seems also able to reduce nuclear expression of Rb in the HOS cells (data not shown).…”

Section: The Neuroprotective Effect Of Sdf-1μ Correlates With the Chasupporting

confidence: 90%

The Chemokine Receptor CXCR4 Regulates Cell-Cycle Proteins in Neurons

Khan

Brandimarti

Musser

et al. 2003

J. of Neurovirology

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Neurons express a variety of chemokine receptors that regulate neuronal signaling and survival, including CXCR4 and CCR5, the two major human immunodeficiency virus (HIV) coreceptors. However, the role of chemokine receptors in HIV neuropathology and neuroinflammatory disorders is still unclear. This study aims to determine whether chemokine receptors regulate the activity of cell-cycle proteins in neurons and evaluate the possibility that alterations of these proteins are involved in HIV neuropathogenesis. The authors studied the effect of the chemokine stromal cellderived factor (SDF)-1α, the natural CXCR4 ligand, and an X4-using variant of gp120 on the activity of cell-cycle proteins involved in neuronal apoptosis and differentiation, such as Rb and E2F-1. Changes in expression, localization, and phosphorylation/activation of Rb and E2F-1 induced by SDF-1α (20 nM) gp120 IIIB (200 pM) were analyzed in primary cultures of rat neurons and in a human cell line expressing recombinant CXCR4. The data indicate that changes in the nuclear and cytosolic levels of Rb-which result in the functional loss of this protein-are associated with apoptosis in hippocampal or cerebellar granule neurons and in cell lines. SDF-1α, which is able to rescue these neurons from apoptosis, induces a time-dependent increase of total Rb expression while decreasing the nuclear content of phosphorylated (Ser780/Ser795) Rb and the transcriptional activity of E2F-1. The HIV envelope protein gp120 IIIB exerts opposite effects at the nuclear level. These data indicate that CXCR4 affects cell-cycle proteins in neurons and raise the possibility that chemokines may contribute to neuronal survival by repressing the activity of E2F-dependent apoptotic genes and maintaining neurons in a highly differentiated and quiescent state. This state may be altered during neuroinflammatory conditions and/or by HIV-derived proteins.

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Section: The Neuroprotective Effect Of Sdf-1μ Correlates With the Chasupporting

confidence: 90%

The Chemokine Receptor CXCR4 Regulates Cell-Cycle Proteins in Neurons

Khan

Brandimarti

Musser

et al. 2003

J. of Neurovirology

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“…Cells cultured on glass coverslips were double-stained with two nuclear fluorochromes, Hoechst 33258, which labels nuclei of all cells, and propidium iodide, which labels nuclei of dead cells, as,~reviouslydescribed (Savio and Levi, 1993). The stained c~iltureswere examined with a Polyvar (Reichert-Jung) ultramicroscope, using AMCA optics to count total cells (blue fluorescent nuclei labeled by Hoechst 33258) and rhodamine optics to count dead cells (red-orange fluorescent nuclei labeled by propidium iodide).…”

Section: Assessment Of Cell Deathmentioning

confidence: 99%

Opposite Regulation of Adenylyl Cyclase by Protein Kinase C in Astrocyte and Microglia Cultures

Patrizio

Slepko

Levi

1997

Journal of Neurochemistry

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Abstract:We studied the regulation of cyclic AMP responses by protein kinase C (PKC) in purified astrocyte and microglia cultures obtained from the neonatal rat brain. In astrocytes, a 1 0-mm treatment with the phorbol esters phorbol 12-myristate 13-acetate (PMA) and 4/3-phorbol 12,13-didecanoate (4/3-PDD) (but not with 4c~-PDD) or with diacyiglycerol, which activate PKC, dosedependently enhanced cyclic AMP accumulation induced by the /3-adrenergic agonist isoproterenol and the adenylyl cyclase activator forskolin. Such enhancement was prevented by the PKC inhibitors staurosporine and calphostin-C and by down-regulation of PKC and was not related to activation of membrane receptors or G~pro-teins or to inhibition of G, proteins or phosphodiesterases. Instead, the activity of adenylyl cyclase doubled in PMAtreated astrocytes. In microglia, a 10-mm treatment with PMA or PKC inhibitors did not affect cyclic AMP accumulation, whereas longer treatments with PMA or 4/3-PDD (but not 4a-PDD) inhibited the cyclic AMP response in a time-and dose-dependent manner. Such inhibition was mimicked by staurosporine and calphostin-C. Also, in the case of microglia, the modulation of cyclic AMP responses appeared to occur at the level of adenylyl cyclase, and not elsewhere in the cyclic AMP cascade. The inhibition of microglial adenylyl cyclase was apparently not due to aspecific cytotoxicity. A differential regulation of adenylyl cyclase by PKC in astrocytes and microglia may help to explain qualitative and quantitative differences in the response of these cells to various physiological and pathological stimuli. Key Words: Cyclic AMPPhorbol ester-Staurosporine--Calphostin-C-G proteins-Phosphodiesterases.

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“…Despite the inability of HIV-1 to infect neurons directly, severe neuronal loss occurs in different brain areas, resulting in multiple types of neurological disorders (Navia et al, 1986;Price et al, 1988;Wiley et al, 1991). In vitro studies on central neurons have found that gp120, probably shed by the virus and/or by infected microglia in vivo, produces neurotoxicity in several types of rodent and human neurons (e.g., hippocampal, retinal ganglion, cortical, and cerebellar granule neurons) (Brenneman et al, 1988;Dreyer et al, 1990;Lipton et al, 1991;Muller et al, 1992;Savio and Levi, 1993). Also, the pathogenic potential of gp120 has been demonstrated in the intact brain by inducing the expression of the viral coat protein in GFAP-gp120 transgenic mice (Toggas et al, 1994).…”

mentioning

confidence: 99%

gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-β1

1996

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We found that TGF-␤1, a cytokine that previously has been reported to have neuroprotective effects, was able to prevent the toxicity induced by the HIV-1 coat protein gp120 in hippocampal pyramidal neuron cultures. In the presence of glia, gp120 induced time-and dose-dependent cell death, which was more pronounced in mature (7-19 d in culture) than in young neurons (2-7 d in culture). Staining with nuclear dyes (propidium iodide and Hoechst 33342), in situ detection of DNA fragments, and DNA analysis on agarose gels indicated that apoptosis was mainly responsible for the death caused by the viral protein. However, after several days of treatment, deathdisplaying necrotic features also occurred. Neurotoxicity induced by gp120 was dependent on the activation of NMDA receptors and required the presence of glia as well as new protein synthesis. Thus, the effect of gp120 was abolished by the NMDA receptor antagonist APV and partially reduced by cycloheximide. Only modest neurotoxicity was observed in pure neuronal cultures deprived of the glia feeder layer. Fura-2-based videoimaging showed that treatment with gp120 enhanced the ability of NMDA to increase neuronal [Ca 2ϩ ] i . The impairment of neuronal Ca 2ϩ homeostasis was prevented completely by TGF-␤1. Therefore, it is likely that the neuroprotective action of the cytokine is attributable to its ability to stabilize neuronal [Ca 2ϩ ] i .

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Neurotoxicity of HIV coat protein gp120, NMDA receptors, and protein kinase C: A study with rat cerebellar granule cell cultures

Cited by 112 publications

References 20 publications

The Chemokine Receptor CXCR4 Regulates Cell-Cycle Proteins in Neurons

The Chemokine Receptor CXCR4 Regulates Cell-Cycle Proteins in Neurons

Opposite Regulation of Adenylyl Cyclase by Protein Kinase C in Astrocyte and Microglia Cultures

gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-β1

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