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Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity


Reference:

Bahia, P. K., Pugh, V., Hoyland, K., Hensley, V., Rattray, M. and Williams, R. J., 2012. Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity. Journal of Neurochemistry, 123 (1), pp. 182-191.

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    Official URL:

    http://dx.doi.org/10.1111/j.1471-4159.2012.07877.x

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    Abstract

    The Forkhead transcription factor, FoxO3a induces genomic death responses in neurones following translocation from the cytosol to the nucleus. Nuclear translocation of FoxO3a is triggered by trophic factor withdrawal, oxidative stress and the stimulation of extrasynaptic NMDA receptors. Receptor activation of phosphatidylinositol 3-kinase (PI3K) - Akt signalling pathways retains FoxO3a in the cytoplasm thereby inhibiting the transcriptional activation of death promoting genes. We hypothesised that phenolic antioxidants such as tert-Butylhydroquinone (tBHQ), which is known to stimulate PI3K-Akt signalling, would inhibit FoxO3a translocation and activity. Treatment of cultured cortical neurones with NMDA increased the nuclear localisation of FoxO3a, reduced the phosphorylation of FoxO3a, increased caspase activity and upregulated Fas ligand expression. In contrast the phenolic antioxidant tBHQ caused retention of FoxO3a in the cytosol coincident with enhanced PI3K- dependent phosphorylation of FoxO3a. tBHQ-induced nuclear exclusion of FoxO3a was associated with reduced FoxO-mediated transcriptional activity. Exposure of neurones to tBHQ inhibited NMDA-induced nuclear translocation of FoxO3a prevented NMDA-induced upregulation of FoxO-mediated transcriptional activity, blocked caspase activation and protected neurones from NMDA-induced excitotoxic death. Collectively, these data suggest that phenolic antioxidants such as tBHQ oppose stress-induced activation of FoxO3a and therefore have potential neuroprotective utility in neurodegeneration. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

    Details

    Item Type Articles
    CreatorsBahia, P. K., Pugh, V., Hoyland, K., Hensley, V., Rattray, M. and Williams, R. J.
    DOI10.1111/j.1471-4159.2012.07877.x
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    URLURL Type
    http://dx.doi.org/10.1111/j.1471-4159.2012.07877.xFree Full-text
    DepartmentsFaculty of Science > Biology & Biochemistry
    Publisher StatementBahia_J_Neuro_Chem_2012_123_182.pdf: © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry
    RefereedYes
    StatusPublished
    ID Code30563

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