Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer’s Disease, Parkinson’s Disease, and Intracerebral Hemorrhage

Abstract

Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has also been implicated in the pathogenesis of Alzheimer’s disease (AD), Parkinson’s disease (PD), and secondary injury following intracerebral hemorrhage (ICH). Chelation of brain iron is thus a promising therapeutic strategy for improving behavioral outcomes and slowing neurodegeneration in the aforementioned disease states, though the effectiveness of DFO treatment is limited on several accounts. Systemically administered DFO results in nonspecific toxicity at high doses, and the drug’s short half-life leads to low patient compliance. Mixed reports of DFO’s ability to cross the blood–brain barrier (BBB) also appear in literature. These limitations necessitate novel DFO formulations prior to the drug’s widespread use in managing neurodegeneration. Herein, we discuss the various dosing regimens and formulations employed in intranasal (IN) or systemic DFO treatment, as well as the physiological and behavioral outcomes observed in animal models of AD, PD, and ICH. The clinical progress of chelation therapy with DFO in managing neurodegeneration is also evaluated. Finally, the elimination of intranasally administered particles via the glymphatic system and efflux transporters is discussed. Abundant preclinical evidence suggests that intranasal DFO treatment improves memory retention and behavioral outcome in rodent models of AD, PD, and ICH. Several other biochemical and physiological metrics, such as tau phosphorylation, the survival of tyrosine hydroxylase-positive neurons, and infarct volume, are also positively affected by intranasal DFO treatment. However, dosing regimens are inconsistent across studies, and little is known about brain DFO concentration following treatment. Systemic DFO treatment yields similar results, and some complex formulations have been developed to improve permeability across the BBB. However, despite the success in preclinical models, clinical translation is limited with most clinical evidence investigating DFO treatment in ICH patients, where high-dose treatment has proven dangerous and dosing regimens are not consistent across studies. DFO is a strong drug candidate for managing neurodegeneration in the aging population, but before it can be routinely implemented as a therapeutic agent, dosing regimens must be standardized, and brain DFO content following drug administration must be understood and controlled via novel formulations.

Dysfunction of the Glymphatic System Might Be Related to Iron Deposition in the Normal Aging Brain

“…The aggregation and deposition of Aβ in perivascular space may affect the bulk flow in perivascular space, directly leading to the dysfunction of the glymphatic system (Mestre et al, 2017). In addition, both iron deposition and dysfunction of the glymphatic system have been implicated in the pathogenesis of Alzheimer's Disease, Parkinson's Disease, and secondary injury following intracerebral hemorrhage, which supports the relationship between iron deposition and glymphatic function (Rasmussen et al, 2018;Farr and Xiong, 2020).…”

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

“…DFO, developed over half a century ago, is the most potent and widely used of several FDA-approved iron chelators [ 17 , 18 ]. These therapeutics were originally developed to address systemic iron overload states such as transfusion-dependent thalassemia major but have since seen significant preclinical and clinical development for use across cancer [ 19 , 20 , 21 ], imaging [ 22 , 23 ], and neurological disease [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. DFO has a short plasma half-life and is typically challenging to deliver systemically, with most delivery methods involving long courses of intravenous (IV) infusion or intramuscular (IM) injection [ 43 ].…”

“…The IN delivery of DFO achieves micromolar concentrations in the brain within minutes and offers up to 200-fold greater targeting compared to IV delivery in rodents [ 24 , 58 ]. In a recent review, Farr and Xiong discuss the formulation and delivery of DFO in detail, tabulating studies performed to date across AD, PD, and intracerebral hemorrhage [ 28 ]. In this review, we cast the spotlight on IN DFO and its therapeutic mechanisms for human neurological disease.…”

“…HIF-1α activates an elaborate transcriptional program designed as an organized cellular response to hypoxia, mediated principally by vascular endothelial growth factor (VEGF), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF) [ 40 , 75 , 76 ]. By these pathways, iron chelators including IN DFO have been found to reverse the accumulation of protein aggregates [ 28 , 30 , 33 , 34 , 77 , 78 , 79 ], suppress neuroinflammation [ 31 , 38 , 77 , 80 , 81 , 82 , 83 , 84 ], protect against oxidative stress and neuronal injury [ 30 , 31 , 32 , 36 , 81 , 83 , 85 ], improve cerebrovascular function [ 25 , 37 , 40 , 76 ], activate pro-survival signaling pathways [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 76 ], bolster cerebral glucose metabolism [ 30 , 31 , 35 ], and strengthen synaptic function [ 35 , 86 , 87 ] ( Figure 1 ). In the follow...…”

“…A seminal two-year single-blind clinical trial found that intramuscular administration of DFO significantly reduced the rate of decline in living skills for AD patients by approximately twofold [ 39 ]. In animal models of AD, evidence for the therapeutic efficacy of DFO, IN DFO, and other iron chelators is very strong and has been reviewed extensively elsewhere [ 28 , 88 ]. From the work of multiple research groups, IN DFO reduces cognitive decline and pathological hallmarks in the APP/PS1, P301L, and ICV STZ rodent models of AD [ 30 , 31 , 33 , 34 , 35 , 36 , 77 , 89 ].…”