Hepcidin plays a key role in 6‐OHDA induced iron overload and apoptotic cell death in a cell culture model of Parkinson’s disease (1038.2)

Elevated brain iron levels have been implicated in the pathogenesis of Parkinson’s disease (PD), however the underlying mechanisms are not clear. Hepcidin, a hormone primarily produced by hepatocytes, acts as a key regulator of cellular iron homeostasis. To investigate hepcidin’s role in 6‐hydroxydopamine (6‐OHDA) induced neurodegeneration, we down regulated hepcidin (32.3% P<0.0001) using siRNA interference technique in N27 dopaminergic neuronal cells and compared with a negative control. Our results show that hepcidin knockdown upregulated ferroportin expression and decreased intracellular free iron as measured with calcein fluorescence quenching method, by 35% and 24% in control and 6‐OHDA treatments. In addition, hepcidin knockdown protected 6‐OHDA induced apoptosis by attenuating oxidative damage. 6‐OHDA increased protein carbonyls by 146.4% (p<0.05), caspase‐3 activity by 154.6% (p<0.001) and DNA fragmentation by 54.3% (p<0.01), whereas hepcidin knockdown almost completely blocked the 6‐OHDA induced protein carbonyls, caspase‐3 activation and DNA fragmentation. Collectively, our results show that hepcidin plays a key role in reducing cellular iron burden and oxidative damage by possibly regulating iron export mediated by ferroprotin. This hepcidin dependent iron regulation in dopaminergic degeneration may provide a novel therapeutic strategy for slowing down the progression of PD.