Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

Rao, Shalini S; Lago, Larissa; Volitakis, Irene; Shukla, Jay J; McColl, Gawain; Finkelstein, David I.; Adlard, Paul A.

doi:10.1007/s13311-020-00972-w

Cited by 18 publications

(13 citation statements)

References 84 publications

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“…Using tau‐overexpressing transgenic mice (rTg4510), deferiprone improved locomotor and memory (Y‐maze) function and attenuated anxiety‐like behaviour in the open‐field test (Rao et al, 2021). An accompanied 28% reduction in brain iron levels was seen, and decreased hippocampal ferritin and phosphorylated tau (Rao et al, 2021). These behavioural and iron‐related changes are consistent with our findings albeit in TBI.…”

Section: Discussionmentioning

confidence: 99%

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Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury

Daglas

Truong

Miles

et al. 2022

British J Pharmacology

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Background and Purpose: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown.Experimental Approach: We investigated the role of iron and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI.Key Results: Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, lipid peroxidation/ oxidative stress and altered expression of neurotrophins in the injured brain over this period. Conclusion and Implications:Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.

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Section: Discussionmentioning

confidence: 99%

“…Short‐term working memory was examined using the Y‐maze, as described previously (Portbury, Hare, Finkelstein, & Adlard, 2017; Rao et al, 2021). The Y‐maze consists of two familiar arms and one novel arm with visual cues along the walls of each arm of the maze.…”

Section: Methodsmentioning

confidence: 99%

Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury

Daglas

Truong

Miles

et al. 2022

British J Pharmacology

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“…We also revealed an anxiogenic-like effect of acute deferiprone in both genotypes. In a mouse model of tauopathy, Rao et al [67] found that chronic deferiprone treatment had an anxiolytic-like effect. However, this was in a model of tauopathy following 16 weeks of treatment and using time spent in the outer arena zone as a measure of anxietylike behaviours, which was substantially different from our acute study.…”

Section: Antidepressant-like Effects Of Deferipronementioning

confidence: 99%

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

et al. 2022

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Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala.

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“…This chelator is likely to act intracellularly [385]. Experimentally, deferiprone has been shown to mobilize Fe deposited in brain [386].…”

Section: Iron Chelation and Other Means To Decrease Cerebral Ironmentioning

confidence: 99%

Cerebral Iron Deposition in Neurodegeneration

et al. 2022

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Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

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Deferiprone Treatment in Aged Transgenic Tau Mice Improves Y-Maze Performance and Alters Tau Pathology

Cited by 18 publications

References 84 publications

Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury

Deferiprone attenuates neuropathology and improves outcome following traumatic brain injury

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Cerebral Iron Deposition in Neurodegeneration

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