Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma

Cui, Qi N.; Bargoud, Albert; Ross, Ahmara G.; Song, Ying; Dunaief, Joshua L.

doi:10.1016/j.exer.2020.107961

Cited by 27 publications

(22 citation statements)

References 38 publications

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“…Iron is crucial for mitochondrial biogenesis, motility, and dynamics in RGCs. The use of iron chelators is protective to RGCs in OHT and optic nerve injury models ( Thaler et al, 2010 ; Cui et al, 2020 ). Previous studies demonstrated that iron deficiency caused by treating cells with iron chelators decreases mitochondrial biogenesis, increases mitochondrial mobility, and inhibits anterograde movement, which impair dendritic outgrowth and synapse formation during neuronal development ( Bastian et al, 2019 ; Upadhyay and Agarwal, 2020 ).…”

Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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Glaucoma is the most substantial cause of irreversible blinding, which is accompanied by progressive retinal ganglion cell damage. Retinal ganglion cells are energy-intensive neurons that connect the brain and retina, and depend on mitochondrial homeostasis to transduce visual information through the brain. As cofactors that regulate many metabolic signals, iron and zinc have attracted increasing attention in studies on neurons and neurodegenerative diseases. Here, we summarize the research connecting iron, zinc, neuronal mitochondria, and glaucomatous injury, with the aim of updating and expanding the current view of how retinal ganglion cells degenerate in glaucoma, which can reveal novel potential targets for neuroprotection.

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Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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“…Amyloid beta promotes iron accumulation in astrocytes, and amyloid beta-induced Lcn2 production is inhibited by deferoxamine treatment (Dekens et al, 2020). Moreover, oral administration of the iron chelator deferiprone protects against RGC and optic nerve loss in glaucoma mouse models with ocular hypertension induced by microbead injections (Cui et al, 2020). Our preliminary study investigating the effect of iron overload on organotypic retinal explant cultures by using cell-permeable ferric 8hydorxyquinoline complex (Fe-8HQ) (Fang et al, 2018) showed that RGC loss became obvious when retinae were treated with Fe-8HQ at doses higher than 100 µM and that TUNEL-positive cells in the presence of 10 µM Fe-8HQ was 4.24-fold higher compared to the untreated control (p ≤ 0.01 vs. control; Supplementary Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Elevated Hydrostatic Pressure Causes Retinal Degeneration Through Upregulating Lipocalin-2

Yoneshige

Hagiyama

Takashima

et al. 2021

Front. Cell Dev. Biol.

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Elevation of intraocular pressure is a major risk factor for glaucoma development, which causes the loss of retinal ganglion cells (RGCs). Lipocalin 2 (Lcn2) is upregulated in glaucomatous retinae; however, whether Lcn2 is directly involved in glaucoma is debated. In this study, retinal explant cultures were subjected to increased water pressure using a two-chamber culture device, and Lcn2 protein levels were examined by immunoblotting. In situ TdT-mediated dUTP nick and labeling (TUNEL) and glial fibrillary acidic protein (GFAP) immunohistochemical assays were performed to assess apoptosis and gliosis, respectively. The neurotoxicity of Lcn2 in the retinal explant culture was determined with exogenous administration of recombinant Lcn2. The Lcn2 protein levels, percentage of TUNEL-positive cells, and GFAP-positive area were significantly higher in retinae cultured under 50 cm H2O pressure loads compared to those cultured under 20 cm H2O. We found that Lcn2 exhibited neurotoxicity in retinae at dose of 1 μg/ml. The negative effects of increased hydrostatic pressure were attenuated by the iron chelator deferoxamine. This is the first report demonstrating the direct upregulation of Lcn2 by elevating hydrostatic pressure. Modulating Lcn2 and iron levels may be a promising therapeutic approach for retinal degeneration.

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“…The microbead occlusion model was used to induce elevated intraocular pressure as described previously ( Cui et al, 2020 ). Briefly, mice were anesthetized with intraperitoneal injections of ketamine (80 mg/kg, Par Pharmaceutical), xylazine (10 mg/kg, Lloyd), and acepromazine (2 mg/kg, Boehringer Ingelheim Vetmedica).…”

Section: Methodsmentioning

confidence: 99%

GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

et al. 2020

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SUMMARY Glaucoma is the leading cause of irreversible blindness and is characterized by the death of retinal ganglion cells (RGCs). Recent studies have implicated pro-inflammatory microglia, macrophages, and A1 astrocytes in the pathogenesis of neurodegenerative diseases. The role of pro-inflammatory, neurotoxic A1 astrocytes in glaucoma is just beginning to be explored. Using a mouse model of glaucoma, we demonstrate that ocular hypertension is sufficient to trigger production of C1q, interleukin-1α (IL-1α), and tumor necrosis factor α (TNF-α), three cytokines necessary and sufficient to drive the formation of A1 astrocytes. Upregulation of these cytokines occurs first in CD11b + CD11c + cells followed by CD11b + CD11c − cells. Ablation of this pathway, by either genetic deletions of C1qa, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduces A1 astrocyte transformation and RGC death. Together, these results highlight a neuroinflammatory mechanism of glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

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Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma

Cited by 27 publications

References 38 publications

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Elevated Hydrostatic Pressure Causes Retinal Degeneration Through Upregulating Lipocalin-2

GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

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