Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs

Authors:

Ljubica Vucicevic1, Maja Misirkic-Marjanovic1, Ljubica Harhaji-Trajkovic1, Nadja Maric2 and Vladimir Trajkovic3
PDF Download PubMed Link
Affiliations:

1 Institute for Biological Research, University of Belgrade, Belgrade, Serbia.

2 Clinic of Psychiatry, Clinical Centre of Serbia and School of Medicine, University of Belgrade, Belgrade, Serbia.

3 Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000  Belgrade, Serbia.

Keywords: 

autophagy, antipsychotics, schizophrenia, neurodegeneration, cancer.

Abbreviations:

AMPK – AMP-activated protein kinase,

ATG – autophagy-related,

LC3 – light chain 3,

mTOR – mammalian target of rapamycin,

ROS – reactive oxygen species,

TFEB – transcription factor EB,

ULK – Unc-51-like autophagy activating kinase.

Corresponding Author(s):

Vladimir Trajkovic, Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia vladimir.trajkovic@med.bg.ac.rs

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Ljubica Vucicevic, Maja Misirkic-Marjanovic, Ljubica Harhaji-Trajkovic, Nadja Maric and Vladimir Trajkovic (2018). Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs. Cell Stress 2(11): 282-291. doi: 10.15698/cst2018.11.161

© 2018 Vucicevic et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

In this review we analyze the ability of antipsychotic medications to modulate macroautophagy, a process of controlled lysosomal digestion of cellular macromolecules and organelles. We focus on its molecular mechanisms, consequences for the function/survival of neuronal and other cells, and the contribution to the beneficial and side-effects of antipsychotics in the treatment of schizophrenia, neurodegeneration, and cancer. A wide range of antipsychotics was able to induce neuronal autophagy as a part of the adaptive stress response apparently independent of mammalian target of rapamycin and dopamine receptor blockade. Autophagy induction by antipsychotics could contribute to reducing neuronal dysfunction in schizophrenia, but also to the adverse effects associated with their long-term use, such as brain volume loss and weight gain. In neurodegenerative diseases, antipsychotic-stimulated autophagy might help to increase the clearance and reduce neurotoxicity of aggregated proteotoxins. However, the possibility that some antipsychotics might block autophagic flux and potentially contribute to proteotoxin-mediated neurodegeneration must be considered. Finally, the anticancer effects of autophagy induction by antipsychotics make plausible their repurposing as adjuncts to standard cancer therapy.