Lactoferrin Reduces Chorioretinal Damage in the Murine Laser Model of Choroidal Neovascularization

Montezuma, Sandra R.; Dolezal, Luke; Rageh, Abrar A.; Mar, Kevin; Jordan, Michael; Ferrington, Deborah A.

doi:10.3109/02713683.2014.969808

Cited by 10 publications

(7 citation statements)

References 28 publications

(29 reference statements)

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“…In the current study, we found that oral administration of lactoferrin has a therapeutic effect in a laser-induced CNV model mimicking the neovascular type of AMD ( Figure 5). This result is consistent with the previous report that the CNV volume is significantly increased in lactoferrin gene knockout mice (Montezuma et al, 2015). It has been reported that HIF downstream genes were upregulated in a laser-irradiated RPE/choroid (Kurihara et al, 2012).…”

Section: Discussionsupporting

confidence: 93%

Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

et al. 2020

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Background: Lactoferrin, a type of glycoprotein, is contained in exocrine fluids such as tears, breast milk, sweat, and saliva, and is known to have anti-microbial, antioxidant, and anti-cancer effects. In the ophthalmological field, topical administration of lactoferrin has been reported to have a therapeutic effect in a murine dry eye model. Hypoxia-inducible factor (HIF) regulates various gene expressions under hypoxia, including vascular endothelial growth factor (VEGF), and is considered as an alternative target for neovascular ocular diseases such as age-related macular degeneration (AMD). We previously screened natural products and identified lactoferrin as a novel HIF inhibitor. In this study, we confirmed that lactoferrin has an HIF inhibitory effect and a therapeutic effect in a murine model of neovascular AMD.Methods: HIF inhibitory effects of lactoferrin were evaluated using a luciferase assay and western blotting in vitro. The quantified volume of choroidal neovascularization (CNV) induced by laser irradiation was compared with oral lactoferrin administration or conditional tissue specific Hif1a knockout mice.Results: Lactoferrin administration showed a significant HIF inhibitory effect in the retinal neuronal cells. Oral administration of lactoferrin or conditional Hif1a gene deletion significantly reduced CNV volume compared to controls.Conclusions: Lactoferrin has a therapeutic effect in a laser CNV model by suppressing the retinal HIF activity.

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Section: Discussionsupporting

confidence: 93%

Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

et al. 2020

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“…Furthermore, treatment of LFKO mice with exogenous LF reduced choroidal neovascularization lesions. 22 Taken together, these results establish the protective roles of LF during ocular wound healing and suggest therapeutic potentials of LF for treating ocular injuries.…”

Section: Introductionmentioning

confidence: 55%

“…Administration of additional exogenous bovine LF can further decrease the chorioretinal damage in the laser induced CNV model in mice. 22 While the mechanism of action remains unclear, it may involve LF’s role in iron binding and subsequent reduction in the Fenton Chemistry reaction that produce damaging hydroxyl radicals by laser insult. Knowing that LF is expressed in the RPE tissue is the first step in identifying the potential mechanism to explain the larger lesion volumes of LFKO versus WT mice.…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin Expression in Human and Murine Ocular Tissue

Rageh¹,

Ferrington²,

Roehrich

et al. 2015

Current Eye Research

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Purpose Lactoferrin (LF) is a multifunctional protein known to provide innate defense due to its antimicrobial and anti-inflammatory properties. In the eye, LF has been identified in the tears and vitreous humor. Its presence in other ocular tissues has not been determined. Our aim is to assess the presence of LF in the cornea, iris, retina and retinal pigment epithelium (RPE) of humans and mice. Methods To test for the endogenous production of LF, reverse transcription polymerase chain reaction was performed in cultured human cells from the cornea and RPE and in murine tissues. To confirm LF localization in specific ocular tissue, immunohistochemistry was performed on flat mounts of cornea, retina and RPE in human donor eyes. The presence of LF was assessed by western blotting in human and mouse ocular tissue and human culture cells (cornea and RPE). To verify antibody specificity, purified human LF and transferrin (TF) were used on 1D and 2D western blots. Results LF gene expression was confirmed in the cornea and RPE cell cultures from humans, suggesting that LF is an endogenously produced protein. PCR results from mouse ocular tissue showed LF expression in cornea, iris, RPE, but not in retina. These results were also consistent with immunohistochemical localization of LF in human donor tissue. Antibody reaction for human LF was specific and western blotting showed its presence in the cornea, iris and RPE tissues. A faint reaction for the retina was observed but was likely due to contamination from other ocular tissues. Multiple commercially available antibodies for murine LF cross-reacted with TF, so no reliable results were obtained for murine western blot. Conclusion LF is expressed in multiple eye tissues of humans and mice. This widespread expression and multifunctional activity of LF suggests that it may play an important role in protecting eye tissues from inflammation-associated diseases.

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“…The mice’s eyes were dilated with 0.5% tropicamide and 0.5% phenylephrine eyedrops (Santen Pharmaceutical, Osaka, Japan) and anesthetized with a combination of midazolam (Sandoz, Tokyo, Japan), medetomidine (Orion, Espoo, Finland), and butorphanol tartrate (Meiji Seika Pharma, Tokyo, Japan), called MMB. The laser procedure was performed as previously reported [38]. To focus on the retina, the eyes of mice were covered with a contact lens (Haag-Streit Diagnostics, Köniz, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Effect of Garcinia cambogia Extract and Hydroxycitric Acid Inhibiting Hypoxia-Inducible Factor in a Murine Model of Age-Related Macular Degeneration

Ibuki

Shoda

Miwa

et al. 2019

IJMS

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Background: Age-related macular degeneration (AMD) is the leading cause of blindness and can be classified into two types called atrophic AMD (dry AMD) and neovascular AMD (wet AMD). Dry AMD is characterized by cellular degeneration of the retinal pigment epithelium, choriocapillaris, and photoreceptors. Wet AMD is characterized by the invasion of abnormal vessels from the choroid. Although anti-vascular endothelial growth factor (VEGF) therapy has a potent therapeutic effect against the disease, there is a possibility of chorio-retinal atrophy and adverse systemic events due to long-term robust VEGF antagonism. We focused on hypoxia-inducible factor (HIF) regulation of VEGF transcription, and report the suppressive effects of HIF inhibition against ocular phenotypes in animal models. Many of the known HIF inhibitors are categorized as anti-cancer drugs, and their systemic side effects are cause for concern in clinical use. In this study, we explored food ingredients that have HIF inhibitory effects and verified their effects in an animal model of AMD. Methods: Food ingredients were screened using a luciferase assay. C57BL6/J mice were administered the Garcinia cambogia extract (Garcinia extract) and hydroxycitric acid (HCA). Choroidal neovascularization (CNV) was induced by laser irradiation. Results: Garcinia extract and HCA showed inhibitory effects on HIF in the luciferase assay. The laser CNV model mice showed significant reduction of CNV volume by administering Garcinia extract and HCA. Conclusions: Garcinia extract and HCA showed therapeutic effects in a murine AMD model.

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Lactoferrin Reduces Chorioretinal Damage in the Murine Laser Model of Choroidal Neovascularization

Cited by 10 publications

References 28 publications

Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

Lactoferrin Has a Therapeutic Effect via HIF Inhibition in a Murine Model of Choroidal Neovascularization

Lactoferrin Expression in Human and Murine Ocular Tissue

Therapeutic Effect of Garcinia cambogia Extract and Hydroxycitric Acid Inhibiting Hypoxia-Inducible Factor in a Murine Model of Age-Related Macular Degeneration

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