Intranasal deferoxamine can improve memory in healthy C57 mice, suggesting a partially non‐disease‐specific pathway of functional neurologic improvement

Abstract

Introduction Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of Alzheimer's and Parkinson's disease. Methods In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline‐treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing. Results We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non‐disease‐specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK‐3β activity and increased HIF‐1α activity. Conclusions These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.

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 ].…”

“…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...…”

“…DFO has been shown to reduce Aβ aggregation [ 31 , 33 , 35 , 77 ] and hyperphosphorylation of tau [ 34 , 101 ], and involvement of transition metals including iron is thought to contribute to the toxicity of these pathological hallmarks [ 70 , 73 ]. DFO is a robust inhibitor of glycogen synthase kinase-3β (GSK-3β) [ 30 , 31 , 32 , 34 ], a well-established therapeutic target in tauopathy, and DFO was found to reverse tau-mediated neurodegeneration in rabbits treated with aluminum [ 101 ]. GSK-3β is also hypothesized as a major link between accumulation of Aβ and consequent hyperphosphorylation of tau in AD [ 91 , 93 , 96 ], placing DFO in position to suppress this acceleratory process.…”

“…DFO also activates glucose transporters including glucose transporter 1 (GLUT1) via HIF-1α [ 35 , 75 , 76 ], countering cerebral hypometabolism that is an early hallmark of AD. Furthermore, DFO has been robustly associated with activation of the insulin signaling pathway [ 30 , 31 , 32 , 34 , 38 ]. Activation of this pathway is known to act on astrocytes, microglia, and neurons to suppress neuroinflammation and promote neuroplasticity [ 102 ], and indeed, intranasal administration of insulin has shown benefit in several Phase 2 AD trials [ 60 , 61 , 62 ].…”

“…Activation of this pathway is known to act on astrocytes, microglia, and neurons to suppress neuroinflammation and promote neuroplasticity [ 102 ], and indeed, intranasal administration of insulin has shown benefit in several Phase 2 AD trials [ 60 , 61 , 62 ]. Finally, there is also precedent for DFO to improve memory in the absence of disease with IN DFO improving memory in healthy mice [ 32 ], possibly via GSK-3β mediated neuroplasticity [ 102 ].…”