Publication: The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy
Issued Date
2010-11-01
Resource Type
ISSN
1600079X
07423098
07423098
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2-s2.0-78349253806
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Pineal Research. Vol.49, No.4 (2010), 382-389
Suggested Citation
Chutikorn Nopparat, James E. Porter, Manuchair Ebadi, Piyarat Govitrapong The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. Journal of Pineal Research. Vol.49, No.4 (2010), 382-389. doi:10.1111/j.1600-079X.2010.00805.x Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/28603
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Title
The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy
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Abstract
Methamphetamine (METH) is a common drug of abuse that induces toxicity in the central nervous system and is connected to neurological disorders such as Parkinsons disease. METH neurotoxicity is induced by reactive oxygen species (ROS) production and apoptosis. Moreover, autophagy is an alternative to cell death and a means for eliminating dysfunctional organelles. In other cases, autophagy can end up in cell death. Nonetheless, it is not clear whether autophagy is also correlated with apoptotic signaling in drug-induced neurotoxicity. Therefore, we hypothesized that METH-generated toxicity associated with initiating the apoptotic signaling cascade can also increase the autophagic phenotype in neuronal cells. Using the SK-N-SH dopaminergic cell line as our model system, we found that METH-induced autophagy by inhibiting dissociation of Bcl-2/Beclin 1 complex and its upstream pathway that thereby led to cell death. We uncovered a novel function for the anti-apoptotic protein Bcl-2, as it played a role in negatively regulating autophagy by blocking an essential protein in the signaling pathway, Beclin 1. Furthermore, Bcl-2 was activated by c-Jun N-terminal kinase 1 (JNK 1), which is upstream of Bcl-2 phosphorylation, to induce Bcl-2/Beclin 1 dissociation. Furthermore, we demonstrated a novel role for melatonin in protecting cells from autophagic cell death triggered by the Bcl-2/Beclin 1 pathway by inhibiting the activation of the JNK 1, Bcl-2 upstream pathway. This study provides information regarding the link between apoptosis and autophagy signaling, which could lead to the development of therapeutic strategies that exploit the neurotoxicity of drugs of abuse. © 2010 The Authors.