Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson’s disease after peripheral administration

Abstract

The iron content of the substantia nigra pars compacta increases in the brains of Parkinson's disease patients. Hence, its removal by iron chelators may retard the progression of the disease. However, information on the ability of clinically available iron chelators to cross the blood brain barrier and be neuroprotective is limited. In this present study three iron chelators, which are currently approved for clinical use, namely the hexadendate, deferrioxamine, the bidentate deferiprone and the tridendate chelator deferasirox have been investigated for their efficacy to induce neuroprotection. Previous studies have shown that both deferiprone and deferrioxamine exert neuroprotection in the 6-hydroxy dopamine (6-OHDA) model but no such studies have investigated deferasirox. Focal administration of deferasirox (0.5, 2 and 10 μg) into the substantia nigra pars compacta of rats significantly attenuated the loss of dopaminergic neurons and striatal dopamine content resulting from 6-OHDA toxicity. Systemic administration of deferasirox (20 mg/kg), deferiprone (10 mg/kg) or deferrioxamine (30 mg/kg), to the 6-OHDA rat model of Parkinson's disease, significantly attenuated the loss of dopaminergic neurons and striatal dopamine content. Further studies to comprehend the action of these chelators showed that local application of either 0.4 mM deferrioxamine, or 1 mM deferasirox, via a microdialysis probe into the striatum, prior to that of 200 μM 6-OHDA, prevented the generation of hydroxyl radicals. Our results confirm that the administration of these chelators show therapeutic efficacy and should be considered as therapeutic agents for the treatment of Parkinson's disease.

Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease

“…Animal studies have shown that iron chelators are able to cross the blood brain barrier and are able to remove excess iron from various brain regions in models of brain iron overload 15–17 . In early studies, we demonstrated that iron chelators, desferrioxamine, deferasirox and deferiprone, currently in clinical use for treating iron overload in thalassemia major, significantly attenuated SNc dopaminergic neuronal and striatal dopamine loss in the 6-hydroxydopamine PD model, whilst reducing hydroxyl radical formation 17 .…”

The neurotoxicity of iron, copper and cobalt in Parkinson’s disease through ROS-mediated mechanisms

“…Some iron chelators have been successfully employed in pre-clinical studies of PD. For example, the natural prototype iron chelator/radical scavenger desferrioxamine (Keberle 1964) and the iron-chelating drugs deferiprone and deferasirox were found to be protective against dopaminergic neurodegeneration induced by iron, 6-OHDA, or MPTP (Ben- Shachar et al , 1991Molina-Holgado et al 2008;Dexter et al 2011). The antibiotic metal chelator clioquinol has been shown to inhibit MPTP-induced neurotoxicity in mice (Kaur et al 2003).…”

Chelating Agents for Neurodegenerative Diseases

“…This therefore represents a suitable animal model to test whether these three chelators are able to cross the BBB and be neuroprotective. In our recent studies [37] we showed that each of these chelators was able to cross the BBB and induce neuroprotection after systemic administration to this animal model. This was exemplified by the preservation of SN dopaminergic cell counts and the normalisation of dopamine metabolism in the striatum.…”