Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells.
Methamphetamine (METH) is a commonly abused drug that damages nerve terminals by causing reactive oxygen species (ROS) formation, apoptosis, and neuronal damage. Autophagy, a type of programmed cell death independent of apoptosis, is negatively regulated by the mammalian target of the rapamycin (mTOR) signaling pathway. It is not known, however, whether autophagy is involved in METH-induced neurotoxicity. Therefore, we investigated the effect of METH on autophagy and its upstream regulator, the mTOR signaling pathway. Using the SK-N-SH dopaminergic cell line, we found that METH induces the expression of LC3-II, a protein associated with the autophagosome membrane, in a dose-dependent manner. Moreover, METH inhibits the phosphorylation of mTOR and the action of its downstream target, the eukaryotic initiation factor (eIF)4E-binding protein, 4EBP1. Melatonin, a major secretory product of pineal, is a potent naturally produced antioxidant that acts through various mechanisms to ameliorate the toxic effects of ROS. We found that a pretreatment with melatonin enhances mTOR activity and 4EBP1 phosphorylation and protects against the formation of LC3-II in SK-N-SH cells exposed to METH. This work demonstrates a novel role for melatonin as a neuroprotective agent against METH.
Kongsuphol
Patthara
P
Center for Neuroscience, Faculty of Science, Mahidol University, Bangkok, Thailand.
Mukda
Sujira
S
Nopparat
Chutikorn
C
Villarroel
Alfredo
A
Govitrapong
Piyarat
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008694:Methamphetamine / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D018797:Cell Cycle Proteins; D000697:Central Nervous System Stimulants; C087000:EIF4EBP1 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D008550:Melatonin