Lutein delays photoreceptor degeneration in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration. There is currently no effective treatment for retinitis pigmentosa. Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration, the role of lutein alone remains unclear. In this study, we administered intragastric lutein to Pde6brd10 model mice, which display degeneration of retinal photoreceptors, on postnatal days 17 (P17) to P25, when rod apoptosis reaches peak. Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control. Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells, in line with an increased survival rate of photoreceptors. Functionally, lutein improved visual behavior, visual acuity, and retinal electroretinogram responses in Pde6brd10 mice. Mechanistically, lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells. The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects. This study was approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. LACUC-20181217-02) on December 17, 2018.

Luteolin delays photoreceptor degeneration in a mouse model of retinitis pigmentosa.

Luteolin is neuroprotective for retinal ganglion cells and retinal pigment epithelial cells after oxidative injury, whereby it can inhibit microglial neurotoxicity. Therefore, luteolin holds the potential to be useful for treatment of retinal diseases. The purpose of this study was to investigate whether luteolin exhibits neuroprotective effects on rod cells in rd10 mice, a slow photoreceptor-degenerative model of retinitis pigmentosa. Luteolin (100 mg/kg) intraperitoneally injected daily from postnatal day 14 (P14) to P25 significantly enhanced the visual performance and retinal light responses of rd10 mice at P25. Moreover, it increased the survival of photoreceptors and improved retinal structure. Mechanistically, luteolin treatment attenuated increases in reactive oxygen species, photoreceptor apoptosis, and reactive gliosis; increased mRNA levels of anti-inflammatory cytokines while lowering that of pro-inflammatory and chemoattractant cytokines; and lowered the ratio of phospho-JNK/JNK. Application of the JNK inhibitor SP600125 exerted a similar protective effect to luteolin, suggesting that luteolin delays photoreceptor degeneration and functional deterioration in rd10 mice through regulation of retinal oxidation and inflammation by inhibiting the JNK pathway. Therefore, luteolin may be useful as a supplementary treatment for retinitis pigmentosa. This study was approved by the Qualified Ethics Committee of Jinan University, China (approval No. IACUC-20181217-02) on December 17, 2018.

Refractive outcomes after intravitreal injection of antivascular endothelial growth factor versus laser photocoagulation for retinopathy of prematurity: a meta-analysis.

OBJECTIVE: To determine the effects of the intraocular injection of antivascular endothelial growth factor (anti-VEGF) drugs on the refractive status of infants with retinopathy of prematurity (ROP). DESIGN: Systematic review and meta-analysis of the refractive status of infants with ROP who receive anti-VEGF drugs. DATA SOURCES: The PubMed, Web of Science and Embase databases and the ClinicalTrials.gov website were searched up to June 2020. ELIGIBILITY CRITERIA WHEN SELECTING STUDIES: We included randomised controlled trials (RCTs) and observational studies that compared refractive errors between anti-VEGF drug and laser therapies. DATA EXTRACTION AND SYNTHESIS: Data extraction and risk-of-bias assessments were conducted by two independent reviewers. We used a random-effect model to pool outcomes. The outcome measures were the spherical equivalents, axial length (AL), anterior chamber depth (ACD) and lens thickness (LT). RESULTS: Thirteen studies involving 1850 eyes were assessed: 914 in the anti-VEGF drug group, and 936 in the control (laser) group. Children who received anti-VEGF drug treatment had less myopia than those who received laser therapy (mean difference=1.80 D, 95% CI 0.97 to 2.63, p＜0.0001, I2=78%). The AL, ACD and LT did not reach statistical significance difference between the two groups. The current evidence indicates that the refractive safety in children with ROP is better for anti-VEGF drug treatment than for laser therapy. CONCLUSIONS: This meta-analysis indicates that anti-VEGF drug therapy results in less myopia compared with laser therapy. However, there are relatively few published articles on refractive errors in ROP, and so high-quality and powerful RCTs are needed in the future. PROSPERO REGISTRATION NUMBER: CRD42020160673.

Current Application of Digital Diagnosing Systems for Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: Retinopathy of prematurity (ROP), a proliferative vascular eye disease, is one of the leading causes of blindness in childhood and prevails in premature infants with low-birth-weight. The recent progress in digital image analysis offers novel strategies for ROP diagnosis. This paper provides a comprehensive review on the development of digital diagnosing systems for ROP to software researchers. It may also be adopted as a guide to ophthalmologists for selecting the most suitable diagnostic software in the clinical setting, particularly for the remote ophthalmic support. METHODS: We review the latest literatures concerning the application of digital diagnosing systems for ROP. The diagnosing systems are analyzed and categorized. Articles published between 1998 and 2020 were screened with the two searching engines Pubmed and Google Scholar. RESULTS: Telemedicine is a method of remote image interpretation that can provide medical service to remote regions, and yet requires training to local operators. On the basis of image collection in telemedicine, computer-based image analytical systems for ROP were later developed. So far, the aforementioned systems have been mainly developed by virtue of classic machine learning, deep learning (DL) and multiple machine learning. During the past two decades, various computer-aided systems for ROP based on classic machine learning (e.g. RISA, ROPtool, CAIER) became available and have achieved satisfactory performance. Further, automated systems for ROP diagnosis based on DL are developed for clinical applications and exhibit high accuracy. Moreover, multiple instance learning is another method to establish an automated system for ROP detection besides DL, which, however, warrants further investigation in future. CONCLUSION: At present, the incorporation of computer-based image analysis with telemedicine potentially enables the detection, supervision and in-time treatment of ROP for the preterm babies.

Lycium barbarum polysaccharides related RAGE and Aß levels in the retina of mice with acute ocular hypertension and promote maintenance of blood retinal barrier.

Our previous study verified the protective effects of Lycium barbarum polysaccharides (LBP) on retinal neurons and blood vessels in acute ocular hypertension (AOH) mice. To investigate the effect of LBP on the reactivity of retinal glial cells, an AOH mouse model was established in one eye by maintaining ocular hypertension of 90 mmHg for 60 minutes. Either LBP solution (1 mg/kg) or phosphate-buffered saline was administrated to the mice by gavage daily, starting 7 days before the AOH insult and continuing until the mice were sacrificed for specimen collection on day 4 post-insult. After AOH insult, increased numbers of astrocytes and microglia were observed, together with decreased expression of the following glial cell biomarkers in the retinal ganglion cells of AOH mice: glial fibrillary acidic protein, glutamine synthetase, aquaporin-4, S-100 proteins, ionized calcium-binding adaptor molecule 1, amyloid precursor protein and receptor of advanced glycosylation end-products. After intervention with LBP, the above changes were significantly reduced. Remarkably, morphological remodeling of blood vessel-associated retinal astrocytes, marked by glial fibrillary acidic protein, was also observed. These results, taken together, suggest that LBP regulated the production of amyloid-ß and expression of receptor of advanced glycosylation end-products, as well as mediating the activity of retinal glial cells, which may lead to the promotion of better maintenance of the blood-retinal barrier and improved neuronal survival in AOH insult. This study was approved by the Committee for the Use of Live Animals in Teaching and Research (approval No. CULTRA-#1664-08).

Normal tension glaucoma: from the brain to the eye or the inverse?

Glaucoma is a chronic, progressive optic neuropathy characterized by the loss of peripheral vision first and then central vision. Clinically, normal tension glaucoma is considered a special subtype of glaucoma, in which the patient's intraocular pressure is within the normal range, but the patient experiences typical glaucomatous changes. However, increasing evidence has challenged the traditional pathophysiological view of normal tension glaucoma, which is based only on intraocular pressure, and breakthroughs in central nervous system imaging may now greatly increase our knowledge about the mechanisms underlying normal tension glaucoma. In this article, we review the latest progress in understanding the pathogenesis of normal tension glaucoma and in developing imaging techniques to detect it, to strengthen the appreciation for the connection between normal tension glaucoma and the brain.

Choosing preclinical study models of diabetic retinopathy: key problems for consideration.

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR.

The current research status of normal tension glaucoma.

Normal tension glaucoma (NTG) is a progressive optic neuropathy that mimics primary open-angle glaucoma, but lacks the findings of elevated intraocular pressure or other mitigating factors that can lead to optic neuropathy. The present review summarized the causes, genetics, and mechanisms underlying NTG in both animal models and human patients. We also proposed that the neurovascular unit is a therapeutic target for NTG management.

Research advances on the usage of traditional Chinese medicine for neuroprotection in glaucoma.

Progressive loss of retinal ganglion cells (RGCs) and their axons is the main pathogenesis of glaucoma. The cause of glaucoma is not fully understood, but the neurodegeneration of glaucoma involves many mechanisms such as oxidative stress, glutamate toxicity and ischemia/reperfusion insult. In order to target these mechanisms, multiple neuroprotective interventions have been investigated to prevent the death of RGCs. Of note are some tonic herbs from the traditional Chinese medicine (TCM) pharmacopeia that have shown neuroprotective effects in glaucoma. TCM differs from Western medicine in that TCM exhibits complicated bioactive components, triggering many signaling pathways and extensive actions on vital organs. Modern scientific approaches have demonstrated some of their underlying mechanisms. In this review, we used Lycium barbarum and Ginkgo biloba as examples to elaborate the characteristics of TCM and their potential applications in neuroprotection in glaucoma.

Protection of retinal ganglion cells and retinal vasculature by Lycium barbarum polysaccharides in a mouse model of acute ocular hypertension.

Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aß and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy.

Progressive retinal degeneration in transgenic mice with overexpression of endothelin-1 in vascular endothelial cells.

PURPOSE: Endothelin-1 (ET-1), synthesized in vascular endothelial cells, is a potent vasoconstrictor. ET-1-related vascular abnormality has been known to be important in the pathogenesis of glaucoma, especially in normal tension glaucoma. However, the long-term effect of increased vascular ET-1 on the retinal tissue is still unclear. METHODS: The mice with overexpression of ET-1 in vascular endothelial cells (TET-1 mice) were examined with the profile of intraocular pressure (IOP), retinal layer thickness, numbers of retinal ganglion cells (RGCs), and axonal changes associated with blood vessel changes. RESULTS: The TET-1 mice exhibited a significant progressive loss of RGCs and decrease of retinal thickness in the inner nuclear layer (INL) and outer nuclear layer (ONL) as early as around 10-12 months. At 24 months, the retinal degeneration became more severe, with around 30% RGC loss associated with thinning of the retinal nerve fiber layer and there was an increase in neuronal loss and thinning of the INL and ONL. In the 24-month-old TET-1 mice, IgG leakage in the blood vessels and decrease in the occludin protein were observed. There was increased glial fibrillary acidic protein expression in the Müller cells. In addition, the astrocytic end-feet on blood vessels were enlarged. The IOP level was normal in all ages (1-24 months) of TET-1 mice. CONCLUSIONS: These data suggested that TET-1 mice may be a useful model to address endothelial ET-1-related mechanisms in vascular-associated retinal degenerative diseases.

Effect of Lycium barbarum Polysaccharides on the expression of endothelin-1 and its receptors in an ocular hypertension model of rat glaucoma.

Lycium barbarum, a traditional Chinese anti-aging herb, has been shown to protect retinal ganglion cells (RGCs) in a rat chronic ocular hypertension (COH) model. Here, we investigated the expression of endothelin-1 (ET-1), a strong vasoconstrictor, and its receptors, ETA and ETB, in the COH model and assessed the effects of Lycium barbarum on the ET-1 axis. Elevated intraocular pressure (IOP) was induced in the right eye of SD rats using argon laser photocoagulation. (1) The expression of ET-1, ETA and ETB in normal and COH retinas was studied. (2) Some COH rats were fed daily with Lycium barbarum Polysaccharides (LBP) using 1 mg/kg or phosphate-buffered saline (PBS) for 3 weeks (started 1 week before photocoagulation). The effects of LBP on the expression of ET-1 and its receptors, ETA and ETB, in COH retina were evaluated. A semi-quantitative analysis of staining intensity was used to evaluate the expression levels of ET-1, ETA and ETB in retinal vasculature. We found that (1) Under COH condition, the immunoreactivity of ET-1 was increased in retina associated with an increase of ETB receptor immunoreactivity and a decrease of ETA receptor immunoreactivity. (2) After feeding COH rats with LBP, the expression of ET-1 was decreased with an increase of ETA expression and a decrease of ETB expression in the retina, especially in RGCs. (3) By comparing the staining intensity in the vasculature of COH retina in LBP-fed group with PBS-fed group, there was a decrease in the expression of ET-1 and ETA and an increase in ETB. In summary, ET-1 expression was up-regulated in the retina in COH model. LBP could decrease the expression of ET-1 and modulate the expression of its receptors, ETA and ETB, under the condition of COH. The neuroprotective effect of LBP on RGCs might be related to its ability to regulate the ET-1-mediated biological effects on RGCs and retinal vasculature.