Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy.
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ABSTRACT:
SUBMITTER: Taveau N
PROVIDER: S-EPMC8080701 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Photoreceptor cell death can cause progressive and irreversible visual impairments. Still, effective therapies on retinal neuroprotection are not available. Hypoxia-inducible factors (HIFs) are transcriptional factors which strongly regulate angiogenesis, erythropoiesis, intracellular metabolism, and programed cell death under a hypoxic or an abnormal metabolic oxidative stress condition. Therefore, we aimed to unravel that inhibition of HIFs could prevent disease progression in photoreceptor cell death, as recent studies showed that HIFs might be pathologic factors in retinal diseases. Adult male balb/cAJcl (8 weeks old; BALB/c) were used to investigate preventive effects of a novel HIF inhibitor halofuginone (HF) on a murine model of light-induced retinopathy. After intraperitoneal injections of phosphate-buffered saline (PBS) or HF (0.4 mg/kg in PBS) for 5 days, male BALB/c mice were subjected to a dark-adaption to being exposed to a white LED light source at an intensity of 3,000 lux for 1 hour in order to induce light-induced retinal damage. After extensive light exposure, retinal damage was evaluated using electroretinography (ERG), optical coherence tomography (OCT), and TUNEL assay. Light-induced retinal dysfunction was suppressed by HF administration. The amplitudes of scotopic a-wave and b-wave as well as that of photopic b-wave were preserved in the HF-administered retina. Outer retinal thinning after extensive light exposure was suppressed by HF administration. Based on the TUNEL assay, cell death in the outer retina was seen after light exposure. However, its cell death was not detected in the HF-administered retina. Halofuginone was found to exert preventive effects on light-induced outer retinal cell death.
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Project description:The purpose of this study was to better understand the role of ocular pigmentation and genetics in light-induced retinal damage. Adult pigmented [Long Evans (LE) and Brown Norway (BN)] and albino [Sprague Dawley (SD) and Lewis (LW)] rats were exposed to a bright cyclic light for 6 consecutive days and where compared with juvenile animals exposed to the same bright light environment from postnatal age 14 to 28. Flash ERGs and retinal histology were performed at predetermined days (D) post-light exposure. At D1, ERGs were similar in all adult groups with no recordable a-waves and residual b-waves. A transient recovery was noticed at D30 in the LW and LE only [b-wave: 18% and 25% of their original amplitude respectively]. Histology revealed that BN retina was the most damaged, while LE retina was best preserved. SD and LW rats were almost as damaged as BN rats. In contrast, the retina of juvenile BN was almost as resistant to the bright light exposure as that of juvenile LE rats. Our results strongly suggest that, although ocular pigmentation and genetic background are important factors in regulating the severity of light-induced retinal damage, the age of the animal at the onset of light exposure appears to be the most important determining factor.
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Project description:Hypoxia-induced retinal neovascularization is a major pathological condition in many vision-threatening diseases. In the present study, we determined whether interleukin (IL)-12, a cytokine that regulates angiogenesis, plays a role in the neovascularization in a mouse model of oxygen-induced retinopathy (OIR). We found that the expressions of the mRNAs of both IL-12p35 and IL-12p40 were significantly reduced in the OIR retinas compared to that of the room air-raised control. The sizes of the avascular areas and neovascular tufts were larger in IL-12p40 knock-out (KO) mice than that in wild type (WT) mice. In addition, an intravitreal injection of recombinant IL-12 reduced both avascular areas and neovascular tufts. IL-12 injection enhanced the expressions of interferon-gamma (IFN-γ) and other downstream chemokines. In an in vitro system, IL-12 had no significant effect on tube formation of human retinal microvascular endothelial cells (HRECs). Moreover, a blockade of IFN-γ suppressed the inhibitory effect of IL-12 on pathological neovascularization. These results suggest that IL-12 plays important roles in inhibiting pathological retinal neovascularization.
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Project description:Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.
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Project description:PurposeRetinal neovascularization is a major cause of blindness. This study aimed to investigate the effects of IL-19 and the underlying mechanisms in a mouse model of oxygen-induced retinopathy (OIR).MethodsC57BL/6J wild-type mice and IL-19 knockout (KO) mice were used to establish an OIR mouse model. Bone marrow-derived macrophages (BMDMs) with or without recombinant IL-19 (rIL-19) stimulation were injected intravitreally. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expressions. ELISA and western blotting were performed to assess the protein levels. Immunofluorescence staining was applied to assess retinal neovascularization. Human retinal endothelial cells (HRECs) stimulated with rIL-19 were cultured to evaluate the effects on cell proliferation and migration.ResultsThe level of IL-19 was significantly elevated at postnatal day 17 in OIR retinas. Both the avascular areas and pathological neovascular tufts were significantly increased in rIL-19-treated OIR retinas and suppressed in IL-19 KO retinas. IL-19 KO mice suppressed expression of ARG1, VEGFA, and pSTAT3. Moreover, BMDMs stimulated by rIL-19 enhanced that expression and suppressed the expression of inducible nitric oxide synthase (iNOS). The proliferation and migration of HRECs were significantly augmented by rIL-19. In addition, intravitreal injection of BMDMs stimulated by rIL-19 enhanced retinal neovascularization.ConclusionsThese findings suggest that IL-19 enhances pathological neovascularization through a direct effect on microvascular endothelial cells and the promotion of M2 macrophage polarization. The inhibition of IL-19 may be a potential treatment for retinal neovascularization.
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Project description:Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3-IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Müller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases.
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Project description:Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. At present, the molecular mechanisms underlying ROP are still far from being clearly understood. Circular RNAs (circRNAs), a novel class of noncoding RNAs, have been reported to serve vital regulatory roles in several human diseases. However, it is still unclear how circRNAs are involved in ROP. In the present study, oxygen-induced retinopathy (OIR) murine retinal samples and paired normal tissues were chosen for high-throughput transcriptome RNA sequencing and bioinformatic analyses. As a result, a total of 236 differentially expressed circRNAs, 14 differentially expressed miRNAs, and 9,756 differentially expressed mRNAs were identified in the OIR samples. Gene ontology analysis showed that angiogenesis ranked in the top five upregulated biological processes associated with differential mRNA expression. Then, 66 co-expression pairs of circRNA-mRNA were predicted according to the mRNAs that were enriched in angiogenesis. Furthermore, coregulation prediction was separately performed to identify the differentially expressed miRNAs that targeted angiogenesis-associated circRNAs or mRNAs. Finally, nine differentially expressed circRNAs were predicted to be competing endogenous RNAs by constructing a circRNA-miRNA-mRNA network followed by reverse transcription-quantitative PCR validation. The results of the present study suggest that the identified set of circRNA transcripts and the potential regulatory mechanisms for the development of ROP are worthy of functional studies.
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Project description:PurposeWe determine if monomethyl fumarate (MMF) can protect the retina in mice subjected to light-induced retinopathy (LIR).MethodsAlbino BALB/c mice were intraperitoneally injected with 50 to 100 mg/kg MMF before or after exposure to bright white light (10,000 lux) for 1 hour. Seven days after light exposure, retinal structure and function were evaluated by optical coherence tomography (OCT) and electroretinography (ERG), respectively. Retinal histology also was performed to evaluate photoreceptor loss. Expression levels of Hcar2 and markers of microglia activation were measured by quantitative PCR (qPCR) in the neural retina with and without microglia depletion. At 24 hours after light exposure, retinal sections and whole mount retinas were stained with Iba1 to evaluate microglia status. The effect of MMF on the nuclear factor kB subunit 1 (NF-kB) and Nrf2 pathways was measured by qPCR and Western blot.ResultsMMF administered before light exposure mediated dose-dependent neuroprotection in a mouse model of LIR. A single dose of 100 mg/kg MMF fully protected retinal structure and function without side effects. Expression of the Hcar2 receptor and the microglia marker Cd14 were upregulated by LIR, but suppressed by MMF. Depleting microglia reduced Hcar2 expression and its upregulation by LIR. Microglial activation, upregulation of proinflammatory genes (Nlrp3, Caspase1, Il-1β, Tnf-α), and upregulation of antioxidative stress genes (Hmox1) associated with LIR were mitigated by MMF treatment.ConclusionsMMF can completely protect the retina from LIR in BALB/c mice. Expression of Hcar2, the receptor of MMF, is microglia-dependent in the neural retina. MMF-mediated neuroprotection was associated with attenuation of microglia activation, inflammation and oxidative stress in the retina.
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Project description:We have recently shown that thioredoxin interacting protein (TXNIP) is required for VEGF-mediated VEGFR2 receptor activation and angiogenic signal. Retinas from TXNIP knockout mice (TKO) exhibited higher cellular antioxidant defense compared to wild type (WT). This study aimed to examine the impact of TXNIP deletion on hyperoxia-induced vaso-obliteration in ischemic retinopathy. TKO and WT pups were subjected to oxygen-induced retinopathy model. Retinal central capillary dropout was measured at p12. Retinal redox and nitrative state were assessed by reduced-glutathione (GSH), thioredoxin reductase activity and nitrotyrosine formation. Western blot and QT-PCR were used to assess VEGF, VEGFR-2, Akt, iNOS and eNOS, thioredoxin expression, ASK-1 activation and downstream cleaved caspase-3 and PARP in retinal lysates. Retinas from TKO mice exposed to hyperoxia showed significant increases (1.5-fold) in vaso-obliteration as indicated by central capillary drop out area compared to WT. Retinas from TKO showed minimal nitrotyrosine levels (10% of WT) with no change in eNOS or iNOS mRNA expression. There was no change in levels of VEGF or activation of VEGFR2 and its downstream Akt in retinas from TKO and WT. In comparison to WT, retinas from TKO showed significantly higher level of GSH and thioredoxin reductase activity in normoxia but comparable levels under hyperoxia. Exposure of TKO to hyperoxia significantly decreased the anti-apoptotic thioredoxin protein (∼ 50%) level compared with WT. This effect was associated with a significant increase in activation of the apoptotic ASK-1, PARP and caspase-3 pathway. Our results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT. This effect resulted in liberation and activation of the apoptotic ASK-1 signal. These findings suggest that TXNIP is required for endothelial cell survival and homeostasis especially under stress conditions including hyperoxia.
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Project description:PurposeRetinal vascular disease represents a major cause for vision loss in the Western world. Recent research has shown that neuronal and vascular damage are closely related in retinal disease. Ciliary neurotrophic factor (CNTF) is a well-studied neurotrophic factor that is currently being tested in clinical trials for the treatment of retinal degenerative diseases and macular telangiectasia. However, little is known about its effect on retinal vasculature. In this study, we investigate the effects of CNTF in retinal neovascular disease using the mouse model of oxygen-induced retinopathy (OIR).MethodsNewborn pups were exposed to 75% oxygen from postnatal day (P)7 to P12 and subsequently returned to room air. Ciliary neurotrophic factor was injected intravitreally at OIR P12 and the vaso-obliterated and neovascular areas were quantified at OIR P17. Immunohistochemistry, RNA, and protein analysis were used to identify CNTF-responsive cells. In vitro experiments were performed to analyze the effect of CNTF on endothelial and astroglial cells.ResultsIn the OIR model, CNTF facilitated capillary regrowth and attenuated preretinal neovascularization in a dose-dependent manner. The protective effect of CNTF was mediated via activation of the JAK/STAT3/SOCS3 signaling pathway. Immunohistochemical studies identified endothelial cells among others as CNTF-responsive cells in the retina. In vitro studies confirmed the anti-angiogenic effect of CNTF on endothelial cell sprouting.ConclusionsThis study provides evidence for a therapeutic potential of CNTF beyond degenerative retinal disease. Vasoproliferative retinopathies may benefit from a CNTF-dependent and SOCS3-mediated angiomodulatory effect.
| S-EPMC4986766 | biostudies-literature