This study aims to investigate erythropoietin (EPO) regulate the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway on the cellular level, thus enhancing the antioxidant capacities of neurons to exert their antiaging effects. The long-range cultured neurons were set as the natural aging cell model, the cellular morphologies, antioxidant capacities and Nrf2 expression changes of naturally aged cells, and the cells that were administrated recombinant human erythropoietin (rh-EPO) and Nrf2 pathway blockers for intervention were observed. EPO intervention could increase Nrf2 expression and Nrf2 nuclear translocation, promote the expression of CuZn superoxide dismutase (SOD), enhance cellular antioxidant capacities, reduce malondialdehyde (MDA) retention and accumulation, thus significantly improving the morphology and neuronal networks of long-range cultured neurons; while LY294002 continuously blocked Nrf2 pathway, rhEPO lost its roles of promoting the proliferation of cytoplasmic Nrf2 protein levels and nuclear translocation of Nrf2. rhEPO could promote CuZn SOD expression, enhance the antioxidant capacities of long-range cultured neurons, increase cell survival by upregulating Nrf2 pathway.

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