Abstract
BackgroundGrowing body of evidence suggests that Parkinson’s disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). Low ceruloplasmin (CP)-ferroxidase activity has been identified in the SN and the cerebrospinal fluid (CSF) of patients with PD. The iron chelator, deferiprone, reduces the abnormally high levels of iron in the SN. In order to determine CP’s involvement in iron accumulation in SN and PD progression, we aim to compare the ability of iron chelation treatment to reducing both SN iron levels and motor handicap in PD patients according to the level of ceruloplasmin activity.MethodsWe used a moderate chelation protocol with deferiprone (DFP) based on a, 6-month delayed-start paradigm, randomized placebo controlled clinical trial in 40 PD patients. CP-ferroxidase activity was determined in blood and CSF together with the D544E gene polymorphism (rs701753). Iron levels were determined by R2* MRI sequence and the motor handicap by the UPDRS motor score.ResultsAfter 6 to 12 months of DFP treatment, greater reductions in SN iron levels and UPDRS motor scores were obtained in patients with higher serum and CSF levels of CP-ferroxidase activity. After 6 months of DFP treatment, the AT genotype group displayed greater reduction of iron level in the SN with greater CSF and serum levels of CP activity than the AA genotype group.ConclusionAlthough most of the DFP-treated patients displayed clinical and radiological improvements, those with the lower CP activity appeared to respond better to iron chelation. Larger RCTs are now needed to establish whether pharmacological modulation of CP activity could be an innovative neuroprotective strategy in PD.Trial registrationFAIR-PARK study (ClinicalTrials.gov reference: NCT00943748; French national reference number: 2008−006842−25). This study was approved by the French Drug Agency (ANSM) and the local institutional review board (“Comité de Protection des Personnes of Lille”).Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0331-3) contains supplementary material, which is available to authorized users.
Highlights
Growing body of evidence suggests that Parkinson’s disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN)
One way of addressing this issue involves comparing the ability of moderate iron chelation treatment to reducing both SN iron levels and United Parkinson’s Disease Rating Scale (UPDRS) scores in PD patients according to the level of ceruloplasmin activity
Deferiprone reduces the abnormally high levels of iron in the SN and the UPDRS motor scores [9]
Summary
Growing body of evidence suggests that Parkinson’s disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). The oxidative damage associated with extrahepatic siderosis is generally attributed to excessive generation of reactive oxygen species following a rise in labile cell iron [1,2] The latter generally attains toxic levels as a result of imbalances between iron ingress, use, storage and Grolez et al BMC Neurology (2015) 15:74 screening of ceruloplasmin gene sequences variations allowed to identify five new missense variations and an already known variation (rs707753), which was not previously identified in PD. One way of addressing this issue involves comparing the ability of moderate iron chelation treatment to reducing both SN iron levels and United Parkinson’s Disease Rating Scale (UPDRS) scores in PD patients according to the level of ceruloplasmin activity. The underlying rationale is that PD patients with lower CP activity might retain more cell iron and respond more favorably to iron chelation therapy
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