| The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. | |
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MedLine Citation:
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PMID: 20738755 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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Methamphetamine (METH) is a common drug of abuse that induces toxicity in the central nervous system and is connected to neurological disorders such as Parkinson's 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. |
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Authors:
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Chutikorn Nopparat; James E Porter; Manuchair Ebadi; Piyarat Govitrapong |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-24 |
Journal Detail:
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Title: Journal of pineal research Volume: 49 ISSN: 1600-079X ISO Abbreviation: J. Pineal Res. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8504412 Medline TA: J Pineal Res Country: Denmark |
Other Details:
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Languages: eng Pagination: 382-9 Citation Subset: IM |
Copyright Information:
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© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S. |
Affiliation:
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Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakornpathom, Thailand. |
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