Protective mechanism of arylpiperazine dopaminergic D2 ligands on nitric oxide and 6-hydroxydopamine induced SH-SY5Y human neuroblastoma cell death

anion (O 2 -• ) content, suggesting that decline in O 2 -• concentration resulted from mitohondrial membrane stabilization.Arylpiperazine 6b did not posses significant O 2 -• scavenging ability.The mechanism underlying the protection provided by the compound 6b was independent of JNK-and ERK-proapoptotic pathways, as 6-OHDA-provoked activation of these proapototic pathways was not modified by arylpiperazine 6b.However, arylpiperazine 6b caused additional transient activation of pro-survival Akt signaling pathway in 6-OHDA-treated cells, which probably contributed to its anti-apoptotic effect.In addition to apoptosis, 6-OHDA induced deleterious autophagy in SH-SY5Y cells by silencing the activity of mTOR, a key autophagy inhibitor in the cell.Arylpiperazine 6b partialy prevented 6-OHDA-triggereddecrease of mTOR activity and autophagy in AMPK-independent manner.Although both compounds showed partial agonist activity on hD2 receptors, their neuroprotective action was independent of dopamine receptor binding, as it was not affected by the high-affinity D1/D2 receptor blocker butaclamol (6a) or selective D2 receptor blocker sulpiride (6b).These results support further study of arylpiperazines as potential neuroprotective drugs.