Research provides new clues about iron toxicity in Parkinson’s disease and explains the paradoxical effect of deferiprone
The results contrast with those of 4 previous independent clinical trials and could provide relevant information on the role of iron accumulation in the process of neurodegeneration.
Treatment with deferiprone in patients with early Parkinson’s disease who have not yet received treatment with levodopa or other dopaminergic drugs, does not provide clinical benefit and, on the contrary, has been associated with a worsening of motor symptoms. This is the conclusion of an international study carried out by the FAIRPARK-II consortium, with the participation of Yaroslau Compta, researcher of the Parkinson’s disease and other neurodegenerative movement disorders: clinical and experimental research group of IDIBAPS, as well as Jaume Kulisevski of the Research Institute of the Hospital de la Santa Cruz y San Pablo and Dolores Vilas of the Hospital Germans Trias i Pujol. The work, coordinated by Compta at the national level, has been published in The New England Journal Of Medicine, accompanied by an editorial on the subject.
Parkinson’s disease is a neurodegenerative disorder that affects millions of people worldwide, and it is characterized by the loss of neurons that produce dopamine, a brain molecule essential for the control of normal body movements. There are several drugs that can supplement the lack of dopamine in these patients and help improve symptoms. However, these drugs do not prevent the loss of neurons or the progression of the disease.
One of the physiological processes that occur in this disease is the abnormal accumulation of iron in the brain. The iron overload has been associated with the loss of dopamine-producing neurons. That is why scientists have been looking for ways to reduce iron in these patients. But, this mineral plays an important role in many biological processes necessary for the normal functioning of the body, for example, the production of dopamine. So, iron can have both beneficial and harmful effects on the body.
Deferiprone is a drug that has the ability to eliminate excess iron in areas where it accumulates abnormally, redistributing it to others that need it. This molecule has been used for a long time to treat iron overload that appears after multiple transfusions in a blood disease called thalassemia.
Apparently contradictory data
Two previous clinical trials involving 40 and 22 patients with newly diagnosed Parkinson’s disease suggested that deferiprone added to treatment with dopamine-supplementing drugs, such as L-DOPA, not only reduced iron overload in the brain, but could improve motor disability.
In the FAIRPARK-II study, led by David Devos at the University Hospital of Lille, France, researchers analysed data from 372 patients with newly diagnosed Parkinson’s disease—when the number of dopamine-producing neurons is still preserved—and still without dopamine supplementation treatment, from 23 European medical centres, including Sant Pau and Clínic Barcelona.
The aim of FAIRPARK was to observe whether deferiprone could be useful in slowing down the progression of Parkinson’s disease or not. Surprisingly, the results showed that after a 36 weeks follow-up, participants who received the treatment had worse scores on the scales to measure the symptoms of the disease, compared to those who received placebo. That is, patients in the control group worsened, but those patients who received deferiprone were even worse.
These findings are in striking contrast to the results of 4 other previous independent clinical trials, where worsening of symptoms was not observed when deferiprone was administered. Researchers believe that dopamine supplementation could be the key. Next steps include now to carry out new combination studies to verify the effects in the initial phases of the disease. So, now, the hypothesis maintains that, in the long run, the reduction of iron is beneficial in slowing down the progression of the disease.
“With this trial we have learned that while, on the one hand, the accumulation of iron in neurons can be deleterious, on the other hand, its increase in the substantia nigra could also be a way to compensate for the lack of dopamine,” explains Compta. “Therefore, in view of the fact that in previous trials where dopaminergic therapy was not excluded, patients did not worsen with deferiprone, we thought that a clinical trial combining both therapies could eliminate the confounding variable of dopaminergic deficit and allow us to adequately assess the potential of deferiprone to modify the course of the disease. This is the next step being considered by the FAIRPARK consortium led by Devos.”
Possible explanation for the paradox
When someone is diagnosed with Parkinson’s disease, around 70% of the neurons that produce dopamine in the brain have already been lost. Thus, the surviving neurons have an overload of work to maintain the necessary levels of dopamine to facilitate the person’s mobility. As mentioned, iron has important functions in the body, and one of them is as a cofactor of the tyrosine-hydroxylase enzyme, essential for the production of dopamine. So, it would be possible that in the early stages of Parkinson’s disease iron is actually helping neurons maintain dopamine production, only becoming toxic in later stages. Therefore, the elimination of iron with drugs such as deferiprone in the initial stages of the disease could explain the worsening of the patients by worsening the production of dopamine, while deferiprone could prevent the harmful effects of iron in later stages, in line with other previous clinical trials.
On the other hand, Levodopa is the immediate precursor of dopamine and does not require tyrosine hydroxylase to be converted into dopamine, quickly replenishing dopamine levels, facilitating the mobility of the person and thus avoiding the negative effect of deferiprone on tyrosine hydroxylase. Therefore, the current hypothesis is that patients treated with levodopa would only see the positive effects of deferiprone through the reduction of harmful levels of accumulated iron, but not its negative effect on dopamine production.
Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, Poewe W, Compta Y, Pavese N, Růžička E, Dušek P, Post B, Bloem BR, Berg D, Maetzler W, Otto M, Habert MO, Lehericy S, Ferreira J, Dodel R, Tranchant C, Eusebio A, Thobois S, Marques AR, Meissner WG, Ory-Magne F, Walter U, de Bie RMA, Gago M, Vilas D, Kulisevsky J, Januario C, Coelho MVS, Behnke S, Worth P, Seppi K, Ouk T, Potey C, Leclercq C, Viard R, Kuchcinski G, Lopes R, Pruvo JP, Pigny P, Garçon G, Simonin O, Carpentier J, Rolland AS, Nyholm D, Scherfler C, Mangin JF, Chupin M, Bordet R, Dexter DT, Fradette C, Spino M, Tricta F, Ayton S, Bush AI, Devedjian JC, Duce JA, Cabantchik I, Defebvre L, Deplanque D, Moreau C; FAIRPARK-II Study Group. Trial of Deferiprone in Parkinson’s Disease. N Engl J Med. 2022 Dec 1;387(22):2045-2055.