Abstract:The effect of side-chain shortening of N/OFQ(1-13)NH 2 at position 9 ([Orn 9 ]N/OFQ(1-13)NH 2 , [Dab 9 ]N/OFQ(1-13)NH 2 , [Dap 9 ]N/OFQ(1-13)NH 2 ) was studied regarding potential toxicity and antioxidant capacity. Staurosporine-and H 2 O 2 -induced damage of SH-SY5Y neuroblastoma cells was not changed in the presence of N/OFQ(1-13)NH 2 and [Orn 9 ]N/OFQ(1-13)NH 2 , but was strongly enhanced in the presence of [Dab 9 ]N/OFQ(1-13)NH 2 and [Dap 9 ]N/OFQ(1-13)NH 2 . Moreover, treatment of cells with the latter two analogues alone led to cell injury. Neuropeptide-dependent differences in the viability of SH-SY5Y cells were also observed, i.e., a cytoprotective effect was observed only in the presence of N/OFQ(1-13)NH 2 and [Orn 9 ]N/OFQ(1-13)NH 2 . Compared to [Dab 9 ]N/OFQ(1-13)NH 2 and [Dap 9 ]N/OFQ(1-13)NH 2 , the effects of N/OFQ(1-13)NH 2 and [Orn 9 ]N/OFQ(1-13)NH 2 were more beneficial in systems generating free oxygen radicals (O 2 -and . OH), as well as on the antioxidant status of rat brain and liver. Taken together, our findings show that N/OFQ(1-13)NH 2 and its structural analogue [Orn 9 ]N/OFQ(1-13)NH 2 possess more favorable profiles than the other two nociceptin (N/OFQ) analogues. The present results suggest that shortening of the side-chain of N/OFQ(1-13)NH 2 might increase cell damage and reduce the viability of SH-SY5Y neuroblastoma cells. Moreover, such alterations may lead to changes in free-oxygen generating systems and in antioxidant status in animal tissues.