TY  - JOUR
AU  - Jovanović-Tucović, Maja
AU  - Harhaji-Trajković, Ljubica
AU  - Dulović, Marija
AU  - Tovilović-Kovačević, Gordana
AU  - Zogović, Nevena
AU  - Jeremić, Marija
AU  - Mandić, Miloš
AU  - Kostić, Vladimir
AU  - Trajković, Vladimir
AU  - Marković, Ivanka
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0014299919306296?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3482
AB  - 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.
T2  - European Journal of Pharmacology
T1  - AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.
VL  - 863
DO  - 10.1016/j.ejphar.2019.172677
SP  - 172677
ER  - 

@article{
author = "Jovanović-Tucović, Maja and Harhaji-Trajković, Ljubica and Dulović, Marija and Tovilović-Kovačević, Gordana and Zogović, Nevena and Jeremić, Marija and Mandić, Miloš and Kostić, Vladimir and Trajković, Vladimir and Marković, Ivanka",
year = "2019",
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.",
journal = "European Journal of Pharmacology",
title = "AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.",
volume = "863",
doi = "10.1016/j.ejphar.2019.172677",
pages = "172677"
}

Jovanović-Tucović, M., Harhaji-Trajković, L., Dulović, M., Tovilović-Kovačević, G., Zogović, N., Jeremić, M., Mandić, M., Kostić, V., Trajković, V.,& Marković, 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.. in European Journal of Pharmacology, 863, 172677.
https://doi.org/10.1016/j.ejphar.2019.172677

Jovanović-Tucović M, Harhaji-Trajković L, Dulović M, Tovilović-Kovačević G, Zogović N, Jeremić M, Mandić M, Kostić V, Trajković V, Marković I. AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy.. in European Journal of Pharmacology. 2019;863:172677.
doi:10.1016/j.ejphar.2019.172677 .

Jovanović-Tucović, Maja, Harhaji-Trajković, Ljubica, Dulović, Marija, Tovilović-Kovačević, Gordana, Zogović, Nevena, Jeremić, Marija, Mandić, Miloš, Kostić, Vladimir, Trajković, Vladimir, Marković, Ivanka, "AMP-activated protein kinase inhibits MPP+-induced oxidative stress and apoptotic death of SH-SY5Y cells through sequential stimulation of Akt and autophagy." in European Journal of Pharmacology, 863 (2019):172677,
https://doi.org/10.1016/j.ejphar.2019.172677 . .