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The Anti-inflammatory Effect of Melatonin on Methamphetamine-Induced Proinflammatory Mediators in Human Neuroblastoma Dopamine SH-SY5Y Cell Lines

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Abstract

Methamphetamine (METH) is a highly addictive drug that is commonly abused worldwide. This psychostimulant drug causes the disturbances in the dopaminergic and serotonergic neurons of several brain areas. Exposure to METH has been shown to induce oxidative stress, reactive oxygen species, reactive nitrogen species, and neuroinflammation. However, the mechanism underlying METH-induced inflammation in neurons is still unclear. In this study, we investigated whether METH caused inflammatory effects in human dopaminergic neuroblastoma SH-SY5Y cells and whether this effect involved the nuclear factor-κB (NF-κB) transcription factor pathway. The present results showed that METH significantly increased inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner and significantly increased the levels of tumor necrosis factor (TNF)-α mRNA and phosphorylated NF-κB, which is translocated into the nucleus. Moreover, our results also show that METH downregulated another transcription factor, the nuclear factor erythroid 2-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Furthermore, we also examined the anti-inflammatory effect of melatonin against these METH-induced neuroinflammatory functions. The results show that melatonin significantly decreases the iNOS protein expression and TNF-α mRNA levels caused by METH. The activation and the level of pNF-κB were decreased while Nrf2 expression was increased when cells were pre-incubated with 100 nM of melatonin. In order to show the relationship between cell death and the increase of iNOS, 100 μM of l-NAME, an iNOS inhibitor pretreatment significantly prevented cell death caused by METH. These results demonstrate, for the first time, that METH directly induces inflammation in neurons via an NF-κB-dependent pathway and that the anti-neuroinflammatory effects of melatonin result from the inhibition of activated NF-κB in parallel with potentiated antioxidant/detoxificant defense by activated Nrf2 pathway.

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Acknowledgments

This study was supported by a scholarship from the University Development Program (UDP) from the Commission on Higher Education to KP, a TRF-Senior Research Scholar Fellowship from the Thailand Research Fund and a Mahidol University Research Grant to PG.

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Authors and Affiliations

  1. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom, 73170, Thailand

    Kannika Permpoonputtana & Piyarat Govitrapong

  2. Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand

    Kannika Permpoonputtana & Piyarat Govitrapong

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  1. Kannika Permpoonputtana
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  2. Piyarat Govitrapong
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Correspondence to Piyarat Govitrapong.

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Permpoonputtana, K., Govitrapong, P. The Anti-inflammatory Effect of Melatonin on Methamphetamine-Induced Proinflammatory Mediators in Human Neuroblastoma Dopamine SH-SY5Y Cell Lines. Neurotox Res 23, 189–199 (2013). https://doi.org/10.1007/s12640-012-9350-7

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  • DOI: https://doi.org/10.1007/s12640-012-9350-7

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