Analogues of desferrioxamine B designed to attenuate iron-mediated neurodegeneration: synthesis, characterisation and activity in the MPTP-mouse model of Parkinson's disease

Gotsbacher, Michael P.; Telfer, Thomas J.; Witting, Paul K.; Double, Kay L.; Finkelstein, David I.; Codd, Rachel

doi:10.1039/c7mt00039a

Cited by 22 publications

(23 citation statements)

References 69 publications

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“…The authors concluded that there was a need to develop safe and effective chelators for therapeutic use. While the aim of this study was to reduce aluminum levels in AD patients, deferoxamine has the capacity to bind several metals such as zinc, copper and iron; the affinity for iron is six times higher than that of aluminum (Gotsbacher et al, 2017 ), therefore it is postulated that the effects seen in the study may have been a result of iron chelation. Indeed, targeting iron has been reported to have therapeutic benefits in clinical trials of PD patients (tau is also disrupted in PD and in animal models of PD).…”

Section: Iron Metabolismmentioning

confidence: 96%

Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration

Rao

Adlard

2018

Front. Mol. Neurosci.

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There is an emerging link between the accumulation of iron in the brain and abnormal tau pathology in a number of neurodegenerative disorders, such as Alzheimer’s disease (AD). Studies have demonstrated that iron can regulate tau phosphorylation by inducing the activity of multiple kinases that promote tau hyperphosphorylation and potentially also by impacting protein phosphatase 2A activity. Iron is also reported to induce the aggregation of hyperphosphorylated tau, possibly through a direct interaction via a putative iron binding motif in the tau protein, facilitating the formation of neurofibrillary tangles (NFTs). Furthermore, in human studies high levels of iron have been reported to co-localize with tau in NFT-bearing neurons. These data, together with our own work showing that tau has a role in mediating cellular iron efflux, provide evidence supporting a critical tau:iron interaction that may impact both the symptomatic presentation and the progression of disease. Importantly, this may also have relevance for therapeutic directions, and indeed, the use of iron chelators such as deferiprone and deferoxamine have been reported to alleviate the phenotypes, reduce phosphorylated tau levels and stabilize iron regulation in various animal models. As these compounds are also moving towards clinical translation, then it is imperative that we understand the intersection between iron and tau in neurodegeneration. In this article, we provide an overview of the key pathological and biochemical interactions between tau and iron. We also review the role of iron and tau in disease pathology and the potential of metal-based therapies for tauopathies.

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Section: Iron Metabolismmentioning

confidence: 96%

Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration

Rao

Adlard

2018

Front. Mol. Neurosci.

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“…Although both radiopharmaceuticals had very similar blood clearance profiles, animals injected with the [ 89 Zr]Zr- D FO*- p -Phe-NCS-trastuzumab demonstrated significantly lower radioactivity levels in liver, spleen, and bone tissue, which was corroborated by small animal PET/CT studies in the same xenograft model. The development of 20 represents a significant achievement in 89 Zr chelator design, and since recent efforts to improve the water solubility of this ligand have been successful the radiopharmaceutical community anxiously awaits its evaluation in a clinical setting [ 109 , 110 , 111 ].…”

Section: The Rationale For New Zirconium-89 Chelation Strategiesmentioning

confidence: 99%

Recent Advances in Zirconium-89 Chelator Development

2018

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The interest in zirconium-89 (89Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used 89Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal®. Despite the prevalence of DFO in 89Zr-immuno-PET applications, the development of new ligands for this radiometal is an active area of research. This review focuses on recent advances in zirconium-89 chelation chemistry and will highlight the rapidly expanding ligand classes that are under investigation as DFO alternatives.

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“…Consistent with that, N-acetyl-l-cysteine (NAC), an antioxidant, which could decrease iron levels, showed neuroprotective effect in PD models [ 61 ]. Moreover, desferrioxamine (DFO) and VAR10303 (VAR), two kinds of iron chelator, reduced the ROS and rescued the MPTP induced PD mouse phenotypes [ 62 , 63 ]. Collectively, iron can also contribute to pathogenesis of PD via aggravating ROS production.…”

Section: Ros and Pd-associated Factorsmentioning

confidence: 99%

The Sources of Reactive Oxygen Species and Its Possible Role in the Pathogenesis of Parkinson’s Disease

Weng

Xie

Liu

et al. 2018

Parkinson's Disease

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Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. The precise mechanism underlying pathogenesis of PD is not fully understood, but it has been widely accepted that excessive reactive oxygen species (ROS) are the key mediator of PD pathogenesis. The causative factors of PD such as gene mutation, neuroinflammation, and iron accumulation all could induce ROS generation, and the later would mediate the dopaminergic neuron death by causing oxidation protein, lipids, and other macromolecules in the cells. Obviously, it is of mechanistic and therapeutic significance to understand where ROS are derived and how ROS induce dopaminergic neuron damage. In the present review, we try to summarize and discuss the main source of ROS in PD and the key pathways through which ROS mediate DA neuron death.

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Analogues of desferrioxamine B designed to attenuate iron-mediated neurodegeneration: synthesis, characterisation and activity in the MPTP-mouse model of Parkinson's disease

Cited by 22 publications

References 69 publications

Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration

Untangling Tau and Iron: Exploring the Interaction Between Iron and Tau in Neurodegeneration

Recent Advances in Zirconium-89 Chelator Development

The Sources of Reactive Oxygen Species and Its Possible Role in the Pathogenesis of Parkinson’s Disease

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