title: Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson׳s disease.
abstract: Deferoxamine (DFO) has shown therapeutic promise for the treatment of Parkinson׳s disease (PD) as it has reduced both behavioral and biochemical deficits when injected into the brain of rodent models of PD. Intranasally administered DFO targets the brain directly but non-invasively and has been effective in animal models of stroke and Alzheimer׳s disease. In this study we sought to determine whether intranasal (IN) DFO could be neuroprotective for PD in a rat model. PD was induced with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, while sham surgery rats received saline injections. Rats were pre-treated three times with either IN DFO or saline (starting 4 days before 6-OHDA), and post-treated twice/wk for one month before behavioral tests. In the apomorphine-induced rotational test, IN DFO significantly decreased the number of contralateral turns after injection of apomorphine HCl (p<0.05). Also, IN DFO significantly decreased limb asymmetry in the rearing tube as measured with contralateral limb touches (p<0.05). The IN DFO treatment yielded a trend towards decreased contralateral foot-slips on the tapered balance beam, though the difference was not significant. Finally, IN DFO-treated rats had increased preservation of tyrosine hydroxylase immunoreactive neurons in the substantia nigra (p<0.05). These results confirm that DFO is beneficial in a 6-OHDA model and demonstrate improvement in motor deficits and dopaminergic neuronal survival with non-invasive intranasal delivery, making this an attractive potential treatment for PD.
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA. Electronic address: jared.m.fine@healthpartners.com.
authors.forename: J M
authors.initials: JM
authors.lastname: Fine
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Forsberg
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Renner
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Faltesek
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Mohan
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Wong
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Arneson
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Crow
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Frey
authors.affiliation: HealthPartners Institute for Education and Research, St Paul, MN, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Hanson
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001058:Apomorphine / Q000494:pharmacology; D003676:Deferoxamine / Q000008:administration & dosage*; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007839:Functional Laterality; D008297:Male; D008474:Medial Forebrain Bundle / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010784:Photomicrography; D020318:Rats, Long-Evans; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D003676:Deferoxamine; D001058:Apomorphine
keywords: Dopamine; Drug-induced rotational test; Iron chelation; Rearing tube; Tapered balance beam; Tyrosine hydroxylase