Indatraline is an antidepressive agent and a non-selective monoamine transporter inhibitor that blocks the reuptake of neurotransmitters (dopamine, serotonin, and norepinephrine). In this study, we report that indatraline induces autophagy via the suppression of mTOR/S6 kinase signaling. Autophagy induction was examined by a cell-based high content screening system using LysoTracker, which was followed by monodansylcadaverine staining and transmission electron microscope observation. Indatraline increased the number of EGFP-LC3 cells expressing autophagosomes in the cytoplasm. Conversion of LC3 was further validated by immunoblotting. Indatraline induced autophagy by affecting the AMPK/mTOR/S6K signaling axis and had no influence on the PI3K/AKT/ERK signaling. Moreover, indatraline induced autophagy in smooth muscle cells (SMCs); further, it exhibited therapeutic potential for restenosis by inhibiting SMC accumulation in a rat restenosis model. These results provide new insights into the role of monoamine transporters in autophagy regulation and identify indatraline as a novel agent for inducing autophagy.
Bibliographical noteFunding Information:
We are grateful to Tamotsu Yoshimori for plasmid encoding EGFP-LC3 and the anti-LC3 antibody. This work was partly supported by grants from the National Research Foundation of Korea, funded by the Korean government (MSIP; 2015K1A1A2028365, 2015M3A9B6027818, 2015M3A9C4676321, 2012M3A9D1054520) and the Brain Korea 21 Plus Project, Republic of Korea. Yoon Sun Cho is supported by the Future Basic Science Research Leader Training Program from NRF.
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