Arylpiperazine dopamineric ligands protect neuroblastoma cells from nitric oxide (NO)-induced mitochondrial damage and apoptosis.
The protective ability of novel arylpiperazine-based dopaminergic ligands against nitric oxide (NO)-mediated neurotoxicity is investigated. The most potent neuroprotective arylpiperazine identified during the study was N-{4-[2-(4-phenyl-piperazin-1-yl)ethyl]-phenyl}picolinamide, which protected SH-SY5Y human neuron-like cells from the proapoptotic effect of NO donor sodium nitroprusside (SNP) by decreasing oxidative stress, mitochondrial membrane depolarization, caspase activation and subsequent phosphatydilserine externalization/DNA fragmentation. The protective effect was associated with the inhibition of proapoptotic (JNK, ERK, AMPK) and activation of antiapoptotic (Akt) signaling pathways, in the absence of interference with intracellular NO accumulation. The neuroprotective action of arylpiperazines was shown to be independent of dopamine receptor binding, as it was not affected by the high-affinity D₁/D₂ receptor blocker butaclamol. These results reported support the further study of arylpiperazines as potential neuroprotective agents.
Institute for Biological Research, University of Belgrade, Despot Stefan Blvd 142, 11000 Belgrade, Serbia.
Gordana
G
Tovilovic
Nevena
N
Zogovic
Ljubica
L
Harhaji-Trajkovic
Maja
M
Misirkic-Marjanovic
Kristina
K
Janjetovic
Ljubica
L
Vucicevic
Sladjana
S
Kostic-Rajacic
Andre
A
Schrattenholz
Aleksandra
A
Isakovic
Vukic
V
Soskic
Vladimir
V
Trajkovic
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D010718:Phosphatidylserines; D010879:Piperazines; D017382:Reactive Oxygen Species; D009599:Nitroprusside; D009569:Nitric Oxide