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Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine.
Autophagy. 2014; 10(12):2362-78.A

Abstract

We investigated the role of autophagy, a controlled cellular self-digestion process, in regulating survival of neurons exposed to atypical antipsychotic olanzapine. Olanzapine induced autophagy in human SH-SY5Y neuronal cell line, as confirmed by the increase in autophagic flux and presence of autophagic vesicles, fusion of autophagosomes with lysosomes, and increase in the expression of autophagy-related (ATG) genes ATG4B, ATG5, and ATG7. The production of reactive oxygen species, but not modulation of the main autophagy repressor MTOR or its upstream regulators AMP-activated protein kinase and AKT1, was responsible for olanzapine-triggered autophagy. Olanzapine-mediated oxidative stress also induced mitochondrial depolarization and damage, and the autophagic clearance of dysfunctional mitochondria was confirmed by electron microscopy, colocalization of autophagosome-associated MAP1LC3B (LC3B henceforth) and mitochondria, and mitochondrial association with the autophagic cargo receptor SQSTM1/p62. While olanzapine-triggered mitochondrial damage was not overtly toxic to SH-SY5Y cells, their death was readily initiated upon the inhibition of autophagy with pharmacological inhibitors, RNA interference knockdown of BECN1 and LC3B, or biological free radical nitric oxide. The treatment of mice with olanzapine for 14 d increased the brain levels of autophagosome-associated LC3B-II and mRNA encoding Atg4b, Atg5, Atg7, Atg12, Gabarap, and Becn1. The administration of the autophagy inhibitor chloroquine significantly increased the expression of proapoptotic genes (Trp53, Bax, Bak1, Pmaip1, Bcl2l11, Cdkn1a, and Cdkn1b) and DNA fragmentation in the frontal brain region of olanzapine-exposed animals. These data indicate that olanzapine-triggered autophagy protects neurons from otherwise fatal mitochondrial damage, and that inhibition of autophagy might unmask the neurotoxic action of the drug.

Authors+Show Affiliations

a Institute for Biological Research ; University of Belgrade ; Belgrade , Serbia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25551567

Citation

Vucicevic, Ljubica, et al. "Autophagy Inhibition Uncovers the Neurotoxic Action of the Antipsychotic Drug Olanzapine." Autophagy, vol. 10, no. 12, 2014, pp. 2362-78.
Vucicevic L, Misirkic-Marjanovic M, Paunovic V, et al. Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine. Autophagy. 2014;10(12):2362-78.
Vucicevic, L., Misirkic-Marjanovic, M., Paunovic, V., Kravic-Stevovic, T., Martinovic, T., Ciric, D., Maric, N., Petricevic, S., Harhaji-Trajkovic, L., Bumbasirevic, V., & Trajkovic, V. (2014). Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine. Autophagy, 10(12), 2362-78. https://doi.org/10.4161/15548627.2014.984270
Vucicevic L, et al. Autophagy Inhibition Uncovers the Neurotoxic Action of the Antipsychotic Drug Olanzapine. Autophagy. 2014;10(12):2362-78. PubMed PMID: 25551567.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine. AU - Vucicevic,Ljubica, AU - Misirkic-Marjanovic,Maja, AU - Paunovic,Verica, AU - Kravic-Stevovic,Tamara, AU - Martinovic,Tamara, AU - Ciric,Darko, AU - Maric,Nadja, AU - Petricevic,Sasa, AU - Harhaji-Trajkovic,Ljubica, AU - Bumbasirevic,Vladimir, AU - Trajkovic,Vladimir, PY - 2015/1/1/entrez PY - 2015/1/1/pubmed PY - 2015/12/15/medline KW - AKT1, v-akt murine thymoma viral oncogene homolog 1 KW - AMPK, AMP-activated protein kinase KW - APAF1, apoptotic protease activating factor 1 KW - ATG, autophagy-related KW - BAD, BCL2-associated agonist of cell death KW - BAK1, BCL2-antagonist/killer 1 KW - BAX, BCL2-associated X protein KW - BBC3, BCL2 binding component 3 KW - BCL2, B-cell CLL/lymphoma 2 KW - BCL2L1, BCL2-like 1 KW - BCL2L11, BCL2-like 11 (apoptosis facilitator) KW - BECN1, Beclin 1, autophagy-related KW - BIRC5, baculoviral IAP repeat containing 5 KW - CDKN1A, cyclin-dependent kinase inhibitor 1A (p21, Cip1) KW - CDKN1B, cyclin-dependent kinase inhibitor 1B (p27, Kip1) KW - CFLAR/FLIP, CASP8 and FADD-like apoptosis regulator KW - COX4I1/COX IV, cytochrome c oxidase IV isoform 1 KW - DEA-NONOate, diethylamine NONOate KW - DHR, dihydrorhodamine 123 KW - FOXO, forkhead box O KW - GABARAP, GABA(A) receptor-associated protein KW - LDH, lactate dehydrogenase KW - MAP1LC3B, microtubule-associated protein 1 light chain 3 β KW - MTOR, mechanistic target of rapamycin KW - PAPA-NONOate, propylamine propylamine NONOate KW - PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1 KW - PTEN, phosphatase and tensin homolog KW - ROS, reactive oxygen species KW - RPS6KB1/S6K1, ribosomal protein S6 kinase, 70kDa, polypeptide 1 KW - SQSTM1 KW - SQSTM1/p62, sequestosome 1 KW - TRP53, transformation related protein 53 (mouse ortholog of human TP53, tumor protein p53) KW - TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling KW - XIAP, X-linked inhibitor of apoptosis KW - antipsychotic KW - apoptosis KW - autophagy KW - mitophagy KW - neurotoxicity KW - nitric oxide, NO KW - olanzapine KW - oxidative stress SP - 2362 EP - 78 JF - Autophagy JO - Autophagy VL - 10 IS - 12 N2 - We investigated the role of autophagy, a controlled cellular self-digestion process, in regulating survival of neurons exposed to atypical antipsychotic olanzapine. Olanzapine induced autophagy in human SH-SY5Y neuronal cell line, as confirmed by the increase in autophagic flux and presence of autophagic vesicles, fusion of autophagosomes with lysosomes, and increase in the expression of autophagy-related (ATG) genes ATG4B, ATG5, and ATG7. The production of reactive oxygen species, but not modulation of the main autophagy repressor MTOR or its upstream regulators AMP-activated protein kinase and AKT1, was responsible for olanzapine-triggered autophagy. Olanzapine-mediated oxidative stress also induced mitochondrial depolarization and damage, and the autophagic clearance of dysfunctional mitochondria was confirmed by electron microscopy, colocalization of autophagosome-associated MAP1LC3B (LC3B henceforth) and mitochondria, and mitochondrial association with the autophagic cargo receptor SQSTM1/p62. While olanzapine-triggered mitochondrial damage was not overtly toxic to SH-SY5Y cells, their death was readily initiated upon the inhibition of autophagy with pharmacological inhibitors, RNA interference knockdown of BECN1 and LC3B, or biological free radical nitric oxide. The treatment of mice with olanzapine for 14 d increased the brain levels of autophagosome-associated LC3B-II and mRNA encoding Atg4b, Atg5, Atg7, Atg12, Gabarap, and Becn1. The administration of the autophagy inhibitor chloroquine significantly increased the expression of proapoptotic genes (Trp53, Bax, Bak1, Pmaip1, Bcl2l11, Cdkn1a, and Cdkn1b) and DNA fragmentation in the frontal brain region of olanzapine-exposed animals. These data indicate that olanzapine-triggered autophagy protects neurons from otherwise fatal mitochondrial damage, and that inhibition of autophagy might unmask the neurotoxic action of the drug. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/25551567/Autophagy_inhibition_uncovers_the_neurotoxic_action_of_the_antipsychotic_drug_olanzapine_ L2 - https://www.tandfonline.com/doi/full/10.4161/15548627.2014.984270 DB - PRIME DP - Unbound Medicine ER -