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Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons

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Abstract

Brain-derived neurotrophic factor (BDNF), in addition to its neurotrophic action, also possesses antioxidant activities. However, the underlying mechanisms remain to be fully defined. Sestrin2 is a stress-responsive gene implicated in the cellular defense against oxidative stress. Currently, the potential functions of sestrin2 in nervous system, in particular its correlation with neurotrophic factors, have not been well established. In this study, we hypothesized that BDNF may enhance sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, and characterized the molecular mechanisms underlying BDNF induction of sestrin2 in primary rat cortical cultures. We found that BDNF-mediated sestrin2 expression in cortical neurons required formation of nitric oxide (NO) with subsequent production of 3′,5′-cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). BDNF induced localization of nuclear factor-kappaB (NF-κB) subunits p65 and p50 into neuronal nuclei that required PKG activities. Interestingly, BDNF exposure led to formation of a protein complex containing at least PKG-1 and p65/p50, which bound to sestrin2 promoter with resultant upregulation of its protein products. Finally, BDNF preconditioning mitigated production of reactive oxygen species (ROS) as a result of 3-NP exposure; this antioxidative effect of BDNF was dependent upon PKG activity, NF-κB, and sestrin2. Taken together, our results indicated that BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-NP through attenuation of ROS formation; furthermore, BDNF induction of sestrin2 requires activation of a pathway involving NO/PKG/NF-κB.

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Acknowledgments

This study was supported by the National Science Council/Ministry of Science and Technology in Taiwan (NSC 101-2314-B-010-042MY2 and MOST 103-2314-B-010-013MY3 to Ding-I Yang), Ministry of Education in Taiwan-Aim for the Top University Plan (104AC-B5 to Ding-I Yang), Department of Health in Taipei City Government (10301-62-003 and 10401-62-022 to Ding-I Yang and Chi-Shin Hwang), and Cheng Hsin General Hospital (103F003C16 and CY10417 to Ding-I Yang and Jiu-Haw Yin).

Conflict of Interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan

    Chia-Lin Wu

  2. Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan

    Chia-Lin Wu & Ding-I Yang

  3. Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Shang-Der Chen

  4. Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Shang-Der Chen

  5. Department of Neurology, Cheng Hsin General Hospital, Taipei, Taiwan

    Jiu-Haw Yin

  6. Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Jiu-Haw Yin

  7. Department of Neurology, Taipei City Hospital, Taipei, Taiwan

    Chi-Shin Hwang

  8. Department of Medicine, National Yang-Ming University, Taipei, Taiwan

    Chi-Shin Hwang

  9. Institute of Brain Science, National Yang-Ming University, Number 155, Section 2, Linong Street, Beitou District, Taipei, 11221, Taiwan

    Ding-I Yang

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  1. Chia-Lin Wu
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Corresponding author

Correspondence to Ding-I Yang.

Electronic Supplementary Material

Supplementary Figures: The entire Western blots shown in the present study, except β-actin, GAPDH, and histone3 that served as the respective loading controls for total proteins, cytosolic proteins, and nuclear proteins, are demonstrated in the corresponding supplementary figures. The numbers on the left side of each blot indicate the molecular weight markers in kDa. Because no immunoblots are presented in Fig. 6, there is no Suppl. Fig. 6.

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Wu, CL., Chen, SD., Yin, JH. et al. Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons. Mol Neurobiol 53, 4126–4142 (2016). https://doi.org/10.1007/s12035-015-9357-1

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  • DOI: https://doi.org/10.1007/s12035-015-9357-1

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