HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

Kunimi, Hiromitsu; Miwa, Yukihiro; Katada, Yusaku; Ohta, Michio

doi:10.7717/peerj.7849

Cited by 17 publications

(22 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on our previous papers, retinal thinning and reduction in RGC number by retinal I/R was suppressed by administration of HIF inhibitors. 13,14 As expected, Hif-1α cKO mice showed significant suppression in retinal thinning (analyzed by total and inner retinal thickness) after I/R, in comparison with that in control mice (Figure 1D-F). When it comes to RGC death, Hif-1α cKO mice had significant suppression of I/R-induced RGC death, in comparison with that in control mice, analyzed by mean number of RGCs between Hif-1α cKO and control mice (Figure 1G,H).…”

Section: Resultssupporting

confidence: 77%

“…Previously, changes in expressions of Hif-1α and the representative HIF target genes such as vascular endothelial growth factor a (Vegfa), glucose transporter 1 (Glut1) and 3-phosphoinositede-dependent protein kinase 1 (Pdk1) were seen in the whole retina by retinal I/R. 13,14 We could reproduce this finding, and upregulated expressions in those genes were suppressed in Hif-1α cKO mice (Figure 1A). Stabilization of HIF-1α was also examined after retinal I/R and there was no induction of HIF-1α in Hif-1α cKO mice (Figure 1B,C).…”

Section: Resultssupporting

confidence: 54%

“…13 Additionally, we found a novel HIF-1α inhibitor halofuginone under our drug screening system, and demonstrated halofuginone inhibited the activation of HIF-1α in the retina and exerted neuroprotective effects in the murine model of retinal I/R. 14 Based on the results from these studies, 13,14 we assumed that HIF induction in retinal ischemia may be linked with inner retinal degeneration including loss of RGCs. To strengthen our findings further, in our current study, we primarily attempted to verify the pathological role of HIF induction in neurodegeneration caused by retinal I/R, by utilizing sensory retina-specific Hif-1α conditional knockout (cKO) mice.…”

Section: Introductionmentioning

confidence: 92%

“…Our previous studies revealed that halofuginone and topotecan suppressed neurodegeneration with significant suppression in Hif-1α upregulation in the whole retina. 13,14 However, changes in its expression and Bnip3 expression have not been studied in the inner retina. Therefore, we firstly extracted inner retinal RNA samples from PBS-administered, halofuginone-administered, topotecan-administered and Chx10-Cre; Hif-1α flox/flox retinas after retinal I/R.…”

Section: Depletion Of Bnip3 In the Inner Retina Weakens Neurodegeneration And Visual Dysfunction After Retinal I/rmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of the HIF‐1α/BNIP3 pathway has a retinal neuroprotective effect

et al. 2021

Self Cite

View full text Add to dashboard Cite

Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.

show abstract

Section: Resultssupporting

confidence: 77%

Section: Resultssupporting

confidence: 54%

Section: Introductionmentioning

confidence: 92%

Section: Depletion Of Bnip3 In the Inner Retina Weakens Neurodegeneration And Visual Dysfunction After Retinal I/rmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of the HIF‐1α/BNIP3 pathway has a retinal neuroprotective effect

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…To identify dietary factors inhibiting HIF and examine the functions against ocular diseases, we have screened natural products and reported their therapeutic effects in animal models of retinal disorders (Kunimi et al, 2019a;Kunimi et al, 2019b;Miwa et al, 2019). We further screened natural products from another library and revealed that administration of Garcinia cambogia extract and its main ingredient hydroxycitric have HIF inhibitory effects, showing significant therapeutic effects in a murine laser-induced CNV model (Ibuki et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Parecoxib sodium alleviates ischemia reperfusion‐induced pulmonary injury via inhibiting ERK/NF‐κB and further activating the HIF‐1α pathway

Guo

Yang

2022

Immunity Inflam & Disease

View full text Add to dashboard Cite

Introduction The lungs are extremely vulnerable to ischemia/reperfusion (I/R), which is characterized by intense inflammation, oxidative stress, alveolar damage, and vascular permeability. Parecoxib sodium (Pare) has been shown to exert protective effects against multiple I/R‐induced tissue injuries. However, its role in I/R‐induced lung injury remains unknown. This study aimed to reveal the roles and mechanisms of Pare in pulmonary I/R injury. Methods Sixty‐six rats were randomly divided into three groups: The sham‐operated group, the pulmonary I/R group, and the Pare‐pretreated I/R group. Pare at 10 mg/kg or saline (vehicle control) were intraperitoneally administered to rats once per day for 5 consecutive days before ischemia. Serum and tissue samples were harvested following 2 h of reperfusion. The oxygenation index (OI) and alveolar‐arterial oxygen partial pressure difference (PA‐aO2) were analyzed. The levels or activities of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, intracellular reactive oxygen species, tumor necrosis factor‐α, interleukin (IL)‐6, and IL‐8 were examined. The mitochondrial membrane potential was measured. The protein expression levels of the extracellular signal‐regulated kinase (ERK), nuclear factor‐κB (NF‐κB) and their phosphorylated forms, and hypoxia‐inducible factor‐1α (HIF‐1α) were detected. Histological changes were observed using hematoxylin and eosin staining. Moreover, the survival rate following pulmonary I/R injury was recorded daily. Results Pare significantly increased the OI, decreased the PA‐aO2, increased the levels of antioxidants, while decreasing the levels of oxidants, and alleviated mitochondrial dysfunction and the histopathological damage induced by I/R. Furthermore, Pare inhibited the expression of proinflammatory cytokines, suppressed the activation of ERK and NF‐κB, further increased HIF‐1α expression, and significantly improved the rat survival rate. Conclusions Pare pretreatment attenuated lung I/R injury by inhibiting oxidative stress and the inflammatory response possibly via inhibiting the activation of the ERK/NF‐κB pathway and further activating the HIF‐1α pathway.

show abstract

HIF inhibitor topotecan has a neuroprotective effect in a murine retinal ischemia-reperfusion model

Cited by 17 publications

References 27 publications

Inhibition of the HIF‐1α/BNIP3 pathway has a retinal neuroprotective effect

Inhibition of the HIF‐1α/BNIP3 pathway has a retinal neuroprotective effect

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

Parecoxib sodium alleviates ischemia reperfusion‐induced pulmonary injury via inhibiting ERK/NF‐κB and further activating the HIF‐1α pathway

Contact Info

Product

Resources

About