title: Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death.
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: Institute for Biological Research, University of Belgrade, Despota Stefana Blvd. 142, 11000 Belgrade, Serbia.
authors: Gordana
authors: G
authors: Tovilovic
authors: Nevena
authors: N
authors: Zogovic
authors: Vukic
authors: V
authors: Soskic
authors: Andre
authors: A
authors: Schrattenholz
authors: Sladjana
authors: S
authors: Kostic-Rajacic
authors: Maja
authors: M
authors: Misirkic-Marjanovic
authors: Kristina
authors: K
authors: Janjetovic
authors: Ljubica
authors: L
authors: Vucicevic
authors: Katarina
authors: K
authors: Arsikin
authors: Ljubica
authors: L
authors: Harhaji-Trajkovic
authors: Vladimir
authors: V
authors: Trajkovic
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D018942:Macrolides; D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines; D034741:RNA, Small Interfering; C522921:picolinaldehyde; D013481:Superoxides; C057620:bafilomycin A; C025946:3-methyladenine; D016627:Oxidopamine; D051057:Proto-Oncogene Proteins c-akt; D000225:Adenine