title: 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.
authors.affiliation: Centre for Neuroscience, Imperial College London, London, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Statton
authors.forename: Charlotte
authors.initials: C
authors.lastname: Whitmore
authors.forename: Wolfhardt
authors.initials: W
authors.lastname: Freinbichler
authors.forename: Peter
authors.initials: P
authors.lastname: Weinberger
authors.forename: Keith F
authors.initials: KF
authors.lastname: Tipton
authors.forename: Laura
authors.initials: L
authors.lastname: Della Corte
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Ward
authors.forename: Robert R
authors.initials: RR
authors.lastname: Crichton
mesh_terms: D000818:Animals; D001565:Benzoates / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects*; D000077588:Deferasirox; D000077543:Deferiprone; D003676:Deferoxamine / Q000008:administration & dosage; D005609:Free Radicals / Q000032:analysis; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007502:Iron Chelating Agents / Q000008:administration & dosage*; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011728:Pyridones / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013011:Sorbic Acid / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D001565:Benzoates; D005609:Free Radicals; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D011728:Pyridones; D014230:Triazoles; D000077543:Deferiprone; D003676:Deferoxamine; D000077588:Deferasirox; D013011:Sorbic Acid