Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood–brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-017-8447-9) contains supplementary material, which is available to authorized users.

Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

“…In the current study we demonstrate the ability of DFP to reduce abnormally high levels of α-SYN in the SH-SY5Y lactacystin cell model of PD. This result adds to recent data showing that DFP is capable of reducing α-SYN aggregation in the hippocampi and cortices of transgenic mice bearing the A53T α-SYN mutation, with such mice that had been fed iron for exacerbating the motor phenotype (Carboni et al 2017). However, the protein reduction effect was weak, with significant variance detected between the mice.…”

Drug Repurposing in Parkinson’s Disease

“…Furthermore, deferiprone has been shown to remove excess labile iron and to attenuate dopaminergic neuronal loss in MPTP mouse models [93]; and inhibit dopaminergic neuron necrosis, ferric ion accumulation and microglial proliferation and reduce the hyperechogenic area of the SN in 6-OHDA rodent models [94,95]. While in a transgenic mouse model overexpressing A53T, deferiprone significantly improved impairments in the rotarod task and the novel object recognition test (though this was not accompanied by changes in α-synuclein aggregation) [96].…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…Deferiprone decreased neuronal cell loss in human dopaminergic neurons in vitro and in MPTP mice by decreasing oxidative stress without interfering with iron-dependent mechanisms [434]. Additionally, deferiprone was able to rescue behavioral deficits and trended to decrease α-syn accumulation in iron-fed A53T α-syn-overexpressing mice [435]. Phase 1 clinical trials of this drug also showed that 12 months of deferiprone administration decreased disease progression in PD patients compared to the placebo group [434].…”