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Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death.
Neuropharmacology. 2013 Sep; 72:224-35.N

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-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3β 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.

Authors+Show Affiliations

Institute for Biological Research, University of Belgrade, Despota Stefana Blvd. 142, 11000 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

23643751

Citation

Tovilovic, Gordana, et al. "Arylpiperazine-mediated Activation of Akt Protects SH-SY5Y Neuroblastoma Cells From 6-hydroxydopamine-induced Apoptotic and Autophagic Death." Neuropharmacology, vol. 72, 2013, pp. 224-35.
Tovilovic G, Zogovic N, Soskic V, et al. Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. Neuropharmacology. 2013;72:224-35.
Tovilovic, G., Zogovic, N., Soskic, V., Schrattenholz, A., Kostic-Rajacic, S., Misirkic-Marjanovic, M., Janjetovic, K., Vucicevic, L., Arsikin, K., Harhaji-Trajkovic, L., & Trajkovic, V. (2013). Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. Neuropharmacology, 72, 224-35. https://doi.org/10.1016/j.neuropharm.2013.04.037
Tovilovic G, et al. Arylpiperazine-mediated Activation of Akt Protects SH-SY5Y Neuroblastoma Cells From 6-hydroxydopamine-induced Apoptotic and Autophagic Death. Neuropharmacology. 2013;72:224-35. PubMed PMID: 23643751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. AU - Tovilovic,Gordana, AU - Zogovic,Nevena, AU - Soskic,Vukic, AU - Schrattenholz,Andre, AU - Kostic-Rajacic,Sladjana, AU - Misirkic-Marjanovic,Maja, AU - Janjetovic,Kristina, AU - Vucicevic,Ljubica, AU - Arsikin,Katarina, AU - Harhaji-Trajkovic,Ljubica, AU - Trajkovic,Vladimir, Y1 - 2013/05/03/ PY - 2012/12/05/received PY - 2013/04/11/revised PY - 2013/04/22/accepted PY - 2013/5/7/entrez PY - 2013/5/7/pubmed PY - 2014/2/12/medline SP - 224 EP - 35 JF - Neuropharmacology JO - Neuropharmacology VL - 72 N2 - 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-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3β 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/23643751/Arylpiperazine_mediated_activation_of_Akt_protects_SH_SY5Y_neuroblastoma_cells_from_6_hydroxydopamine_induced_apoptotic_and_autophagic_death_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(13)00183-4 DB - PRIME DP - Unbound Medicine ER -