TY  - JOUR
AU  - Tovilović-Kovačević, Gordana
AU  - Zogović, Nevena
AU  - Šoškić, Vukić
AU  - Schrattenholz, Andre
AU  - Kostić-Rajačić, Slađana
AU  - Misirkić Marjanović, Maja
AU  - Janjetović, Kristina
AU  - Vučićević, Ljubica
AU  - Arsikin, Katarina
AU  - Harhaji-Trajković, Ljubica
AU  - Trajković, Vladimir
PY  - 2013
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6343
AB  - We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SHSY5Y neuroblastoma cells from the neurotoxin 6-hydroxydopamine (6-OHDA). The compound with the most potent neuroprotective action was N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), which reduced 6-OHDA-induced apoptotic death through stabilization of mitochondrial membrane and subsequent prevention of superoxide production, caspase activation and DNA fragmentation. 6-OHDA-triggered autophagic response was also reduced by 6b, which prevented inactivation of the main autophagy repressor mTOR, upregulation of proautophagic beclin-1, conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3b gene silencing or pharmacological autophagy blockers 3-methyladenine or bafilomycin A1, mimicked the cytoprotective effect of 6b. While the treatment with 6b had no effect on the phosphorylation of proapoptotic MAP kinases ERK and JNK, it markedly increased the phosphorylation of the prosurvival kinase Akt in 6-OHDA-treated cells. Akt inhibitor DEBC or RNA interference-mediated Akt silencing reduced the ability of 6b to block 6-OHDA-triggered apoptotic and autophagic responses, thus confirming their dependency on Akt activation. The cytoprotective effect of 6b was also observed in 6-OHDA-treated neuronal PC12 cells, but not in SH-SY5Y or PC12 cells exposed to 1-methyl-4-phenylpyridinium, indicating that the observed neuroprotection was dependent on the cytotoxic stimulus. Because of the ability to prevent 6-OHDA induced apoptotic/autophagic cell death through activation of Akt, the investigated arylpiperazines could be potential candidates for treatment of neurodegenerative diseases.
PB  - Elsevier Ltd.
T2  - Neuropharmacology
T1  - Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death
VL  - 72
DO  - 10.1016/j.neuropharm.2013.04.037
SP  - 224
EP  - 235
ER  - 

@article{
author = "Tovilović-Kovačević, Gordana and Zogović, Nevena and Šoškić, Vukić and Schrattenholz, Andre and Kostić-Rajačić, Slađana and Misirkić Marjanović, Maja and Janjetović, Kristina and Vučićević, Ljubica and Arsikin, Katarina and Harhaji-Trajković, Ljubica and Trajković, Vladimir",
year = "2013",
abstract = "We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SHSY5Y neuroblastoma cells from the neurotoxin 6-hydroxydopamine (6-OHDA). The compound with the most potent neuroprotective action was N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), which reduced 6-OHDA-induced apoptotic death through stabilization of mitochondrial membrane and subsequent prevention of superoxide production, caspase activation and DNA fragmentation. 6-OHDA-triggered autophagic response was also reduced by 6b, which prevented inactivation of the main autophagy repressor mTOR, upregulation of proautophagic beclin-1, conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3b gene silencing or pharmacological autophagy blockers 3-methyladenine or bafilomycin A1, mimicked the cytoprotective effect of 6b. While the treatment with 6b had no effect on the phosphorylation of proapoptotic MAP kinases ERK and JNK, it markedly increased the phosphorylation of the prosurvival kinase Akt in 6-OHDA-treated cells. Akt inhibitor DEBC or RNA interference-mediated Akt silencing reduced the ability of 6b to block 6-OHDA-triggered apoptotic and autophagic responses, thus confirming their dependency on Akt activation. The cytoprotective effect of 6b was also observed in 6-OHDA-treated neuronal PC12 cells, but not in SH-SY5Y or PC12 cells exposed to 1-methyl-4-phenylpyridinium, indicating that the observed neuroprotection was dependent on the cytotoxic stimulus. Because of the ability to prevent 6-OHDA induced apoptotic/autophagic cell death through activation of Akt, the investigated arylpiperazines could be potential candidates for treatment of neurodegenerative diseases.",
publisher = "Elsevier Ltd.",
journal = "Neuropharmacology",
title = "Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death",
volume = "72",
doi = "10.1016/j.neuropharm.2013.04.037",
pages = "224-235"
}

Tovilović-Kovačević, G., Zogović, N., Šoškić, V., Schrattenholz, A., Kostić-Rajačić, S., Misirkić Marjanović, M., Janjetović, K., Vučićević, L., Arsikin, K., Harhaji-Trajković, L.,& Trajković, V.. (2013). Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. in Neuropharmacology
Elsevier Ltd.., 72, 224-235.
https://doi.org/10.1016/j.neuropharm.2013.04.037

Tovilović-Kovačević G, Zogović N, Šoškić V, Schrattenholz A, Kostić-Rajačić S, Misirkić Marjanović M, Janjetović K, Vučićević L, Arsikin K, Harhaji-Trajković L, Trajković V. Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. in Neuropharmacology. 2013;72:224-235.
doi:10.1016/j.neuropharm.2013.04.037 .

Tovilović-Kovačević, Gordana, Zogović, Nevena, Šoškić, Vukić, Schrattenholz, Andre, Kostić-Rajačić, Slađana, Misirkić Marjanović, Maja, Janjetović, Kristina, Vučićević, Ljubica, Arsikin, Katarina, Harhaji-Trajković, Ljubica, Trajković, Vladimir, "Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death" in Neuropharmacology, 72 (2013):224-235,
https://doi.org/10.1016/j.neuropharm.2013.04.037 . .