Reduced hepcidin expression leads to iron accumulation in the substantia nigra of rotenone-induced rat model of Parkinson's disease.

Despite years of research, it is still unclear why iron accumulates in the substantia nigra (SN) of Parkinson's disease (PD) animal models and PD patients. To address this, we investigated the changes in serum iron, iron content, transferrin receptor (TfR1), ferroportin 1 (Fpn1), hepcidin, and iron regulatory proteins (IRPs) expression in the SN, and hepcidin in serum and cerebrospinal fluid (CSF) in rotenone-induced PD rat model, as well as iron content and hepcidin in rotenone-induced PD cell models. We demonstrate that rotenone induces PD-like dyskinesia, dopaminergic neuron loss, as well as increases iron and decreases hepcidin in the SN on days 10 and 30 after injection, and also increases iron in rotenone-induced PD cell models. At 30 days after rotenone injection, TfR1 expression increased and Fpn1 decreased, while 10 days after injection, TfR1 expression decreased and Fpn1 increased in the SN. Decreased hepcidin was also found in serum and CSF of rotenone treated rats, and in rotenone-treated SH-SY5Y cells and primary mesencephalic neurons. We conclude that PD-like movement disorders in rats are closely related to the loss of dopaminergic neurons, which may be associated with increased iron in the SN of rats in vivo, suggesting that hepcidin reduction may be one of the causes of iron accumulation in the SN, affecting the expression of cellular iron transport proteins at the late stage (30 days) after rotenone injection.