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Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-κB and Nrf2 Pathways in Glioma Cell Line

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Abstract

Methamphetamine (METH) is known as a toxin for neuronal and glial cells. Previous studies have found that METH-induced glial cell death and inflammation is mediated by oxidative stress. However, the exact mechanisms of the inflammatory response remain unclear. Therefore, we hypothesized that the activation of nuclear factor-κB (NF-κB) signaling, a key mediator of inflammation, and the inhibition of nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, a regulator of the antioxidant response, would be significant events occurring in response to METH-induced inflammation in a rat glioma cell line (C6 cells). Our results show that METH increased the production of nitric oxide (NO) and up-regulated the expression of its main regulatory protein, inducible nitric oxide synthase (iNOS). METH also induced NF-κB activation by increasing inhibitory κBα (IκBα) degradation and translocation of the NF-κB (p65) subunit into the nucleus. Additionally, METH inhibited the activation of the Nrf2 pathway by decreasing the translocation of Nrf2 into the nucleus and also by suppressing the expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), resulting in the suppression of superoxide dismutase (SOD) activity. Pretreatment with melatonin effectively promoted Nrf2 activation and reversed the METH-induced NF-κB response. Melatonin increased the expression of HO-1, NQO-1, and γ-GCLC, resulting in increased SOD activity. In addition, melatonin also decreased IκBα degradation, translocation of the p65 subunit, and expression of iNOS, resulting in decreased NO production. Taken together, our results indicate that melatonin diminishes the proinflammatory mediator in METH-stimulated C6 cells by inhibiting NF-κB activation and inducing Nrf2-mediated HO-1, NQO-1, and γ-GCLC expression.

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Acknowledgments

This work was supported by the Faculty of Medicine, Chiang Mai University, Thailand and a research Grant from the Thailand Research Fund (TRF) through RMU 5480011 to JT and by research Grants from TRF (DPG5780001) and Mahidol University to PG.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Pichaya Jumnongprakhon & Chainarong Tocharus

  2. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand

    Piyarat Govitrapong

  3. Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Piyarat Govitrapong

  4. Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Decha Pinkaew & Jiraporn Tocharus

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  1. Pichaya Jumnongprakhon
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Correspondence to Jiraporn Tocharus.

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Jumnongprakhon, P., Govitrapong, P., Tocharus, C. et al. Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-κB and Nrf2 Pathways in Glioma Cell Line. Neurochem Res 40, 1448–1456 (2015). https://doi.org/10.1007/s11064-015-1613-2

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  • DOI: https://doi.org/10.1007/s11064-015-1613-2

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