Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease

Guillaume Grolez, Caroline Moreau, Bernard Sablonnière, Guillaume Garçon, Jean-Christophe Devedjian, Sayah Meguig, Patrick Gelé, Christine Delmaire, Regis Bordet, Luc Defebvre, Ioav Z Cabantchik, David Devos, Guillaume Grolez, Caroline Moreau, Bernard Sablonnière, Guillaume Garçon, Jean-Christophe Devedjian, Sayah Meguig, Patrick Gelé, Christine Delmaire, Regis Bordet, Luc Defebvre, Ioav Z Cabantchik, David Devos

Abstract

Background: Growing 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.

Methods: We 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.

Results: After 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.

Conclusion: Although 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 registration: FAIR-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").

Figures

Figure 1
Figure 1
Flowchart of the patients who participated to the clinical trial and to the ceruloplasmin analysis.
Figure 2
Figure 2
Ceruloplasmin activity and iron chelation treatment. (A) Effect of the iron chelator DFP on CSF levels of CP-ferroxidase activity. The patients in the ES group (n = 11 with two lumbar punctures: at baseline and at 6 months) displayed significantly higher CSF levels of CP activity than the patients in the DS group (F(1,16)=13; p=0.002 (B) Effect of the iron chelator DFP on serum levels of CP-ferroxidase activity. The patients in the ES group showed significantly higher serum levels of CP activity than the patients in the DS group at 6 months (F(1,35)=26; p=0.0001) and 12 months (F(1,34)=5.2; p=0.028) but not at 18 months. (C) Effect of the iron chelator DFP on CSF levels of CP-ferroxidase activity as a function of D544E genotype. The DFP-treated patients with an AT genotype (n = 5) displayed significantly higher CSF levels of CP activity than the DFP-treated patients with an AA genotype (n = 6) (F(1,8)=7; p=0.02). (D) Effect of the iron chelator DFP on serum levels of CP-ferroxidase activity as a function of D544E genotype. The DFP-treated patients with an AT genotype (AT; n = 5) displayed significantly higher levels of CP activity than DFP-treated patients with an AA genotype (AA; n = 15) at 6 months (F(1,17)=7; p=0.02) but not at 12 or 18 months. (E) Correlation between CSF levels of CP-ferroxidase activity and the R2* MRI value in the SN. The change in CSF levels of CP activity between the baseline and the visit at 12 months were significantly correlated with the change in the SN’s R2* value (r=0.784; p=0.001). White circles represent the DFP-treated patients with an AA genotype. Grey circles represent the DFP-treated patients with an AA genotype with an AT genotype; the latter displayed higher levels of CP activity and a greater reduction in R2* in the SN.

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