Fullerene antioxidants decrease organophosphate-induced acetylcholinesterase inhibition in vitro

Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA.
Toxicology in Vitro (Impact Factor: 2.9). 09/2010; 25(1):301-7. DOI: 10.1016/j.tiv.2010.09.010
Source: PubMed


Although organophosphate (OP)-induced acetylcholinesterase (AChE) inhibition is the critical mechanism causing toxicities that follow exposure, other biochemical events, including oxidative stress, have been reported to contribute to OP toxicity. Fullerenes are carbon spheres with antioxidant activity. Thus, we hypothesized that fullerenes could counteract the effects of OP compounds and tested this hypothesis using two in vitro test systems, hen brain and human neuroblastoma SH-SY5Y cells. Cells were incubated with eight different derivatized fullerene compounds before challenge with paraoxon (0=control, 5×10(-8), 10(-7), 2×10(-7) or 5×10(-7) M) or diisopropylphosphorofluoridate (DFP, 0=control, 5×10(-6), 10(-5), 2×10(-5), and 5×10(-5) M) and measurement of AChE activities. Activities of brain and SH-SY5Y AChE with OP compounds alone ranged from 55-83% lower than non-treated controls after paraoxon and from 60-92% lower than non-treated controls after DFP. Most incubations containing 1 and 10 μM fullerene derivatives brought AChE activity closer to untreated controls, with improvements in AChE activity often >20%. Using dissipation of superoxide anion radicals as an indicator (xanthine oxidation as a positive control), all fullerene derivatives demonstrated significant antioxidant capability in neuroblastoma cells at 1 μM concentrations. No fullerene derivative at 1 μM significantly affected neuroblastoma cell viability, when determined using either Alamar Blue dye retention or a luminescent assay for ATP production. These studies suggest that derivatized fullerene nanomaterials have potential capability to ameliorate OP-induced AChE inhibition resulting in toxicities.

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    • "In addition to its antioxidant properties, fullerenols were demonstrated to modulate the inhibition of acetylcholinesterase activity caused by certain toxic compounds in vitro [85] and were protective towards NMDA, AMPA, GABA, and KA receptors under conditions of increased oxidative stress [60, 74, 77]. Recent studies by Zha et al. [86] suggested that fullerenol protects hippocampal neurons from damage but may also induce cell death in certain doses, indicating a concentration-/dose-dependent effect. "
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    ABSTRACT: Recently, much attention has been paid to the bioactive properties of water-soluble fullerene derivatives: fullerenols, with emphasis on their pro- and antioxidative properties. Due to their hydrophilic properties and the ability to scavenge free radicals, fullerenols may, in the future, provide a serious alternative to the currently used pharmacological methods in chemotherapy, treatment of neurodegenerative diseases, and radiobiology. Some of the most widely used drugs in chemotherapy are anthracycline antibiotics. Anthracycline therapy, in spite of its effective antitumor activity, induces systemic oxidative stress, which interferes with the effectiveness of the treatment and results in serious side effects. Fullerenols may counteract the harmful effects of anthracyclines by scavenging free radicals and thereby improve the effects of chemotherapy. Additionally, due to the hollow spherical shape, fullerenols may be used as drug carriers. Moreover, because of the existence of the currently ineffective ways for neurodegenerative diseases treatment, alternative compounds, which could prevent the negative effects of oxidative stress in the brain, are still sought. In the search of alternative methods of treatment and diagnosis, today's science is increasingly reaching for tools in the field of nanomedicine, for example, fullerenes and their water-soluble derivatives, which is addressed in the present paper.
    BioMed Research International 09/2013; 2013:751913. DOI:10.1155/2013/751913 · 2.71 Impact Factor
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    • "The ATCA is mostly cleared from the body after seven days as demonstrated above. Similarly, the TMS were recently shown to have a favorable toxicity profile in vitro and in vivo[12]. Since it is anticipated that a patient will only be given a single injection before CMR is performed, these results are encouraging for future studies in humans. "
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    ABSTRACT: Background The hallmark of atherosclerosis is the accumulation of plaque in vessel walls. This process is initiated when monocytic cells differentiate into macrophage foam cells under conditions with high levels of atherogenic lipoproteins. Vulnerable plaque can dislodge, enter the blood stream, and result in acute myocardial infarction and stroke. Imaging techniques such as cardiovascular magnetic resonance (CMR) provides one strategy to identify patients with plaque accumulation. Methods We synthesized an atherosclerotic-targeting contrast agent (ATCA) in which gadolinium (Gd)-containing endohedrals were functionalized and formulated into liposomes with CD36 ligands intercalated into the lipid bilayer. In vitro assays were used to assess the specificity of the ATCA for foam cells. The ability of ATCA to detect atherosclerotic plaque lesions in vivo was assessed using CMR. Results The ATCA was able to detect scavenger receptor (CD36)-expressing foam cells in vitro and were specifically internalized via the CD36 receptor as determined by focused ion beam/scanning electron microscopy (FIB-SEM) and Western blotting analysis of CD36 receptor-specific signaling pathways. The ATCA exhibited time-dependent accumulation in atherosclerotic plaque lesions of ApoE −/− mice as determined using CMR. No ATCA accumulation was observed in vessels of wild type (C57/b6) controls. Non-targeted control compounds, without the plaque-targeting moieties, were not taken up by foam cells in vitro and did not bind plaque in vivo. Importantly, the ATCA injection was well tolerated, did not demonstrate toxicity in vitro or in vivo, and no accumulation was observed in the major organs. Conclusions The ATCA is specifically internalized by CD36 receptors on atherosclerotic plaque providing enhanced visualization of lesions under physiological conditions. These ATCA may provide new tools for physicians to non-invasively detect atherosclerotic disease.
    Journal of Cardiovascular Magnetic Resonance 01/2013; 15(1):7. DOI:10.1186/1532-429X-15-7 · 4.56 Impact Factor
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    Artificial Intelligence Systems, 2002. (ICAIS 2002). 2002 IEEE International Conference on; 02/2002
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