Interferon Gamma Potentiates the Injury Caused by MPP(+) on SH-SY5Y Cells, Which is Attenuated by the Nitric Oxide Synthases Inhibition

Titze‐de‐Almeida, Simoneide Souza; Lustosa, Cátia; Horst, Camila Hillesheim; Bel, Elaine Del; Titze‐de‐Almeida, Ricardo

doi:10.1007/s11064-014-1449-1

Cited by 14 publications

(9 citation statements)

References 51 publications

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“…At the second 24-h incubation period, the addition of caffeine to IFN-γ-stimulated cells in glutamine-free medium significantly enhanced the toxicity of 5 μ M MeHg. This result is in accordance with the findings of Titze-de-Almeida et al (57) and Vikman et al (58). Thus, Vikman et al indicated that when the neurons were treated with IFN-γ, neurophysiological alterations could be observed 48 h following exposure, when the frequency of AMPA receptor-mediated spontaneous excitatory post-synaptic currents are increased (58).…”

Section: Discussionsupporting

confidence: 94%

“…IFN-γ is a pro-inflammatory cytokine that plays a pivotal role in the pathology of diseases in the CNS (20). Titze-de-Almeida et al demonstrated that IFN-γ sensitized SH-SY5Y cells to neurotoxin-induced injury, also causing an increase in ROS levels (57). Furthermore, IFN-γ directly induces neuronal dysfunction and enhances glutamate neurotoxicity mediated by AMPA receptors, but not NMDA receptors (20).…”

Section: Discussionmentioning

confidence: 99%

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Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Engin

Golokhvast

et al. 2017

International Journal of Molecular Medicine

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The molecular mechanisms mediating mercury-induced neurotoxicity are not yet completely understood. Thus, the aim of this study was to investigate whether the severity of MeHg- and HgCl2-mediated cytotoxicity to SH-SY5Y human dopaminergic neurons can be attenuated by regulating glutamate-mediated signal-transmission through caffeine and interferon-γ (IFN-γ). The SH-SY5Y cells were exposed to 1, 2 and 5 μM of either MeHgCl2 or HgCl2 in the presence or absence of L-glutamine. To examine the effect of adenosine receptor antagonist, the cells were treated with 10 and 20 μM caffeine. The total mitochondrial metabolic activity and oxidative stress intensity coefficient were determined in the 1 ng/ml IFN-γ- and glutamate-stimulated SH-SY5Y cells. Following exposure to mercury, the concentration-dependent decrease in mitochondrial metabolic activity inversely correlated with oxidative stress intensity. MeHg was more toxic than HgCl2. Mercury-induced neuronal death was dependent on glutamate-mediated excitotoxicity. Caffeine reduced the mercury-induced oxidative stress in glutamine-containing medium. IFN-γ treatment decreased cell viability and increased oxidative stress in glutamine-free medium, despite caffeine supplementation. Although caffeine exerted a protective effect against MeHg-induced toxicity with glutamate transmission, under co-stimulation with glutamine and IFN-γ, caffeine decreased the MeHg-induced average oxidative stress only by half. Thereby, our data indicate that the IFN-γ stimulation of mercury-exposed dopaminergic neurons in neuroinflammatory diseases may diminish the neuroprotective effects of caffeine.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Engin

Golokhvast

et al. 2017

International Journal of Molecular Medicine

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“…Proliferating or differentiated SH-SY5Y cells are a human cellular model extensively used to explore molecular effects of neuroactive compounds (Alboni et al 2013;Dias et al 2014;Titze-de-Almeida et al 2014;Wang et al 2014) as well as to study mechanisms underlying neurodegenerative diseases in humans (Chiu et al 2015;Feng et al 2014;Pimenova et al 2014;Zheng et al 2013). Here, to our knowledge, we characterized for the first time, through HR-MAS NMR analysis, the metabolic fingerprint of intact human neuronal SH-SY5Y cells and their culture medium.…”

Section: Discussionmentioning

confidence: 99%

Changes in the NMR Metabolic Profile of Live Human Neuron-Like SH-SY5Y Cells Exposed to Interferon-α2

Righi

Schenetti

Mucci

et al. 2015

J Neuroimmune Pharmacol

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Interferon (IFN)-α2 is an extensively therapeutically used pro-inflammatory cytokine. Though its efficacy in controlling viral replication and tumor cells proliferation, administration of IFN-α2 is often associated with the development of central side effects. Magnetic resonance spectroscopy studies have demonstrated that IFN-α2 administration affects brain metabolism, however the exact nature of this effect is not completely known. We hypothesized that IFN-α2 can affect metabolic activity of human neuron-like SH-SY5Y cells which possess many characteristics of neurons and represent one of the most used models for studying mechanisms involved in neurotoxicity or neuroprotection. To test our hypothesis we have characterized the metabolic signature of live SH-SY5Y, and their conditioned media, after 24 and 72 h of exposure to vehicle or IFN-α2 (100 ng/ml) by using High Resolution-Magic Angle Spinning (HR-MAS) Nuclear Magnetic Resonance (NMR) spectroscopy. Our results revealed that 1) the use of HR-MAS NMR is ideally suitable for the characterization of the metabolic profile of live cells and their conditioned media without extraction procedures; and 2) a 72 h exposure to IFN-α2 increases the level of metabolites involved in maintaining energetic (including creatine and lactate) and osmotic (such as myo-inositol, scyllo-inositol, taurine and glycerophosphorylcholine) balances in neuron-like cells and of metabolic waste products (namely lactate, ethanol and acetate), glycine and glutamine in their growth media. These results may contribute to gain more knowledge about the IFN-α2 induced effect on the brain and support the interpretation of magnetic resonance spectroscopy studies performed in humans.

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“…locked nucleic acids), as well as the development of novel carriers for siRNA delivery (78). The oligonucleotide siRNAnNOShum_4400 used in the present study has no phosphorothioate backbones and locked nucleic acids (23). Thus, we recommend adopting these chemical changes in future studies with nNOS-targeted siRNAs for improvements in the specificity and duration of silencing effects.…”

Section: Discussionmentioning

confidence: 99%

“…The present study used a previously described siRNA named siRNAnNOShum_4400, which targets an nNOS mRNA sequence identified by the BIOPREDsi algorithm (22,23 ), according to the manufacturer's protocol. The effect of siRNAnNOShum_4400 on nNOS mRNA content was determined by RT-qPCR as described below.…”

Section: Cellmentioning

confidence: 99%

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

Resende

Titze‐de‐Almeida

2018

Oncol Lett

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Abstract. Astrocytic tumors, including astrocytomas and glioblastomas, are the most common type of primary brain tumors. Treatment for glioblastomas includes radiotherapy, chemotherapy with temozolomide (TMZ) and surgical ablation. Despite certain therapeutic advances, the survival time of patients is no longer than 12-14 months. Cancer cells overexpress the neuronal isoform of nitric oxide synthase (nNOS). In the present study, it was examined whether the nNOS enzyme serves a role in the damage of astrocytoma (U251MG and U138MG) and glioblastoma (U87MG) cells caused by TMZ. First, TMZ (250 µM) triggered an increase in oxidative stress at 2, 48 and 72 h in the U87MG, U251MG and U138MG cell lines, as revealed by 2',7'-dichlorofluorescin-diacetate assay. The drug also reduced cell viability, as measured by MTT assay. U87MG cells presented a more linear decline in cell viability at time-points 2, 48 and 72 h, compared with the U251MG and U138MG cell lines. The peak of oxidative stress occurred at 48 h. To examine the role of NOS enzymes in the cell damage caused by TMZ, N(ω)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) were used. L-NAME increased the cell damage caused by TMZ while reducing the oxidative stress at 48 h. The preferential nNOS inhibitor 7-NI also improved the TMZ effects. It caused a 12.8% decrease in the viability of TMZ-injured cells. Indeed, 7-NI was more effective than L-NAME in restraining the increase in oxidative stress triggered by TMZ. Silencing nNOS with a synthetic small interfering (si)RNA (siRNAnNOShum_4400) increased by 20% the effects of 250 µM of TMZ on cell viability (P<0.05). Hoechst 33342 nuclear staining confirmed that nNOS knock-down enhanced TMZ injury. In conclusion, our data reveal that nNOS enzymes serve a role in the damage produced by TMZ on astrocytoma and glioblastoma cells. RNA interference with nNOS merits further studies in animal models to disclose its potential use in brain tumor anticancer therapy.

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Interferon Gamma Potentiates the Injury Caused by MPP(+) on SH-SY5Y Cells, Which is Attenuated by the Nitric Oxide Synthases Inhibition

Cited by 14 publications

References 51 publications

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Changes in the NMR Metabolic Profile of Live Human Neuron-Like SH-SY5Y Cells Exposed to Interferon-α2

Function of neuronal nitric oxide synthase enzyme in temozolomide-induced damage of astrocytic tumor cells

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