Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway

  • Sci Rep. 2016 Oct 3;6:34655. doi: 10.1038/srep34655.
Yoon Sun Cho  1 ,  Chih-Na Yen  1 ,  Joong Sup Shim  2  3 ,  Dong Hoon Kang  4 ,  Sang Won Kang  4 ,  Jun O Liu  2 ,  Ho Jeong Kwon  1  5
Affiliations
  • 1. Chemical Genomics Global Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
  • 2. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USA.
  • 3. Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
  • 4. Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 5. Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
PMID: 27694974 DOI: 10.1038/srep34655
Abstract

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.

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