The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy
Version of Record online: 24 AUG 2010
© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S
Journal of Pineal Research
Volume 49, Issue 4, pages 382–389, November 2010
How to Cite
Nopparat, C., Porter, J. E., Ebadi, M. and Govitrapong, P. (2010), The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. Journal of Pineal Research, 49: 382–389. doi: 10.1111/j.1600-079X.2010.00805.x
- Issue online: 18 OCT 2010
- Version of Record online: 24 AUG 2010
- Received May 27, 2010; accepted July 16, 2010.
- Beclin 1;
- reactive oxygen species
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 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.