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Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death

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2013
Authors
Tovilović, Gordana
Zogovic, Nevena
Šoškić, Vukić
Schrattenholz, Andre
Kostić Rajačić, Slađana
Misirkić-Marjanović, Maja
Janjetovic, Kristina
Vucicevic, Ljubica
Arsikin, Katarina
Harhaji-Trajković, Ljubica
Trajković, Vladimir
Article (Published version)
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Abstract
We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SH-SY5Y 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-associAed LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3 beta 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 ERR 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 6-0HDA-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.

Keywords:
Arylpiperazine / 6-Hydroxydopamine / Neuroprotection / Akt / Autophagy / Apoptosis
Source:
Neuropharmacology, 2013, 72, 224-235
Publisher:
  • Pergamon-Elsevier Science Ltd, Oxford
Projects:
  • The role of autophagy in regulation of cancer cell death (RS-173053)
  • Modulation of intracellular energy balance-controlling signalling pathways in therapy of cancer and neuro-immuno-endocrine disorders (RS-41025)
  • UNESCO L'OREAL national scholarship program "For Women in Science" - 403F

DOI: 10.1016/j.neuropharm.2013.04.037

ISSN: 0028-3908

PubMed: 23643751

WoS: 000321941800025

Scopus: 2-s2.0-84884827950
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15
URI
http://cer.ihtm.bg.ac.rs/handle/123456789/1201
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IHTM

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