Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor inhibit ferrous iron influx via divalent metal transporter 1 and iron regulatory protein 1 regulation in ventral mesencephalic neurons

Iron accumulation is observed in the substantia nigra of patients with Parkinson's disease. However, it is unknown whether neurotrophic factors, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) participate in the modulation of neuronal iron metabolism. Here, we investigated the effects and underlying mechanisms of BDNF and GDNF on the iron influx process in primary cultured ventral mesencephalic neurons. 6-hydroxydopamine-induced enhanced ferrous iron influx via improper up-regulation of divalent metal transporter 1 with iron responsive element (DMT1 + IRE) was consistently relieved by BDNF and GDNF. Both the mRNA and protein levels of DMT1 + IRE were down-regulated by BDNF or GDNF treatment alone. We further demonstrated the involvement of iron regulatory protein 1 (IRP1) in BDNF- and GDNF-induced DMT1 + IRE expression. Extracellular-regulated kinase 1/2 (ERK1/2) and Akt were activated and participated in these processes. Inhibition of ERK1/2 and Ala phosphorylation abolished the down-regulation of IRP1 and DMT1 + IRE induced by BDNF and GDNF. Taken together, these results show that BDNF and GDNF ameliorate iron accumulation via the ERK/Akt pathway, followed by inhibition of IRP1 and DMT1 + IRE expression, which may provide new targets for the neuroprotective effects of these neurotrophic factors. (C) 2014 Elsevier B.V. All rights reserved.