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AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.
Eur J Pharmacol. 2019 Nov 15; 863:172677.EJ

Abstract

We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy.

Authors+Show Affiliations

Institute of Medical and Clinical Biochemistry, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia.Department of Neurophysiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd. 142, 11000, Belgrade, Serbia.Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Straβe 1, 23562, Lübeck, Germany.Department of Biochemistry, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd 142, 11000, Belgrade, Serbia.Department of Biochemistry, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despot Stefan Blvd 142, 11000, Belgrade, Serbia.Institute of Medical and Clinical Biochemistry, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia.Institute of Microbiology and Immunology, University of Belgrade, Dr Subotica 1, 11000, Belgrade, Serbia.Clinic for Neurology CCS, University of Belgrade, Dr Subotica 6, 11000, Belgrade, Serbia.Institute of Microbiology and Immunology, University of Belgrade, Dr Subotica 1, 11000, Belgrade, Serbia. Electronic address: vladimir.trajkovic@med.bg.ac.rs.Institute of Medical and Clinical Biochemistry, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia. Electronic address: ivanka.markovic@med.bg.ac.rs.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31542478

Citation

Jovanovic-Tucovic, Maja, et al. "AMP-activated Protein Kinase Inhibits MPP+-induced Oxidative Stress and Apoptotic Death of SH-SY5Y Cells Through Sequential Stimulation of Akt and Autophagy." European Journal of Pharmacology, vol. 863, 2019, p. 172677.
Jovanovic-Tucovic M, Harhaji-Trajkovic L, Dulovic M, et al. AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy. Eur J Pharmacol. 2019;863:172677.
Jovanovic-Tucovic, M., Harhaji-Trajkovic, L., Dulovic, M., Tovilovic-Kovacevic, G., Zogovic, N., Jeremic, M., Mandic, M., Kostic, V., Trajkovic, V., & Markovic, I. (2019). AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy. European Journal of Pharmacology, 863, 172677. https://doi.org/10.1016/j.ejphar.2019.172677
Jovanovic-Tucovic M, et al. AMP-activated Protein Kinase Inhibits MPP+-induced Oxidative Stress and Apoptotic Death of SH-SY5Y Cells Through Sequential Stimulation of Akt and Autophagy. Eur J Pharmacol. 2019 Nov 15;863:172677. PubMed PMID: 31542478.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy. AU - Jovanovic-Tucovic,Maja, AU - Harhaji-Trajkovic,Ljubica, AU - Dulovic,Marija, AU - Tovilovic-Kovacevic,Gordana, AU - Zogovic,Nevena, AU - Jeremic,Marija, AU - Mandic,Milos, AU - Kostic,Vladimir, AU - Trajkovic,Vladimir, AU - Markovic,Ivanka, Y1 - 2019/09/19/ PY - 2019/07/31/received PY - 2019/09/11/revised PY - 2019/09/18/accepted PY - 2019/9/23/pubmed PY - 2020/3/24/medline PY - 2019/9/23/entrez KW - AMPK KW - Akt KW - Autophagy KW - MPP+ KW - Neurons KW - Oxidative stress SP - 172677 EP - 172677 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 863 N2 - We investigated the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), prosurvival kinase Akt, oxidative stress, and autophagy in the cytotoxicity of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) towards SH-SY5Y human neuroblastoma cells. MPP+-mediated oxidative stress, mitochondrial depolarization, and apoptotic cell death were associated with rapid (within 2 h) activation of AMPK, its target Raptor, and prosurvival kinase Akt. Antioxidants N-acetylcysteine and butylated hydroxyanisole suppressed MPP+-induced cytotoxicity, AMPK, and Akt activation. A genetic or pharmacological inhibition of AMPK increased MPP+-triggered production of reactive oxygen species and cell death, and diminished Akt phosphorylation, while AMPK activation protected SH-SY5Y cells from MPP+. On the other hand, genetic or pharmacological inactivation of Akt stimulated MPP+-triggered oxidative stress and neurotoxicity, but did not affect AMPK activation. At later time-points (16-24 h), MPP+ inhibited the main autophagy repressor mammalian target of rapamycin, which coincided with the increase in the levels of autophagy marker microtubule-associated protein 1 light-chain 3B. MPP+ also increased the concentration of a selective autophagic target sequestosome-1/p62 and reduced the levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification, suggesting that MPP+-induced autophagy was coupled with a decrease in autophagic flux. Nevertheless, further pharmacological inhibition of autophagy sensitized SH-SY5Y cells to MPP+-induced death. Antioxidants and AMPK knockdown reduced, whereas genetic inactivation of Akt potentiated neurotoxin-triggered autophagy. These results suggest that MPP+-induced oxidative stress stimulates AMPK, which protects SH-SY5Y cells through early activation of antioxidative Akt and late induction of cytoprotective autophagy. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/31542478/AMP_activated_protein_kinase_inhibits_MPP+_induced_oxidative_stress_and_apoptotic_death_of_SH_SY5Y_cells_through_sequential_stimulation_of_Akt_and_autophagy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(19)30629-6 DB - PRIME DP - Unbound Medicine ER -