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Review
. 2021 Jan 27;14(2):95.
doi: 10.3390/ph14020095.

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

Jacob Kosyakovsky  1   2 , Jared M Fine  2 , William H Frey 2nd  2 , Leah R Hanson  2
Affiliations
Review

Mechanisms of Intranasal Deferoxamine in Neurodegenerative and Neurovascular Disease

Jacob Kosyakovsky et al. Pharmaceuticals (Basel). .

Abstract

Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.

Keywords: Alzheimer’s disease; Parkinson’s disease; brain iron dyshomeostasis; deferoxamine; intracranial hemorrhage; intranasal; iron chelation; ischemic stroke.

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Conflict of interest statement

W.H.F.II and L.R.H. are inventors on a patent owned by HealthPartners Institute related to intranasal deferoxamine. J.K. and J.M.F. have no competing interests.

Figures

Figure 1
Figure 1
The disease-nonspecific mechanisms of iron chelation using intranasal deferoxamine (IN DFO). Depletion of brain iron engages a number of disease-relevant pathways.
Figure 2
Figure 2
Putative mechanisms of IN DFO in Alzheimer’s disease. IN DFO engages Alzheimer’s pathogenesis at multiple levels, including a number of contributory aging-related processes, amyloid misprocessing, tau misprocessing, amyloid-tau interaction, neuroinflammation, neurovascular dysfunction, and neurodegeneration.
Figure 3
Figure 3
Putative mechanisms of IN DFO in Parkinson’s disease. IN DFO engages pathways that limit age-related processes such as iron accumulation, α-synuclein misprocessing, neuroinflammation, neurovascular dysfunction, and neurodegeneration to counter the Parkinson’s pathological process and loss of dopaminergic neurons.
Figure 4
Figure 4
Putative mechanisms of IN DFO in ischemic stroke. IN DFO bolsters the brain’s intrinsic hypoxic response, contributing to immediate neuroprotection, improved cerebrovascular function, and ischemic preconditioning to minimize the impact of future occlusive events.
Figure 5
Figure 5
Putative mechanisms of IN DFO in intracranial hemorrhage. IN DFO minimizes the impact of heme- and iron-mediated neurotoxicity following hematoma.
See this image and copyright information in PMC

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