Comparative evaluation of four Lycium barbarum cultivars on NaIO3-induced retinal degeneration mice via multivariate statistical analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Lycium barbarum L. (goji berry) is a traditional Chinese medicine and is often used to improve vision. While various goji cultivars may differentially treat retinal degeneration, however their comparative effectiveness remains unclear. AIM OF THE STUDY: To evaluate the protective effects of four goji cultivars on NaIO3-induced retinal degeneration mouse model and identify the most therapeutically potent cultivar. MATERIALS AND METHODS: The principal compounds in the extracts of four goji cultivars were characterized by UPLC-Q-TOF/MS. A retinal degeneration mouse model was established via NaIO3 injection. Dark-light transition and TUNEL assays were used to assess visual function and retinal apoptosis. The levels of antioxidative, inflammatory, and angiogenic markers in serums and eyeballs were measured. Hierarchical cluster analysis, principal component analysis and partial least squares-discriminant analysis were used to objectively compare the treatment responses. RESULTS: Sixteen compounds were identified in goji berry extracts. All goji berry extracts could reverse NaIO3-induced visual impairment, retinal damage and apoptosis. The samples from the cultivar of Ningqi No.1 significantly modulated oxidative stress, inflammation, and vascular endothelial growth factor levels, which are more effectively than the other cultivars based on integrated multivariate profiling. CONCLUSION: Ningqi No.1 demonstrated a stronger protective effect on mouse retina than other goji cultivars, and is a potential variety for further research on the treatment of retinal degeneration.

Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells by WNT Switch Method.

The differentiation of ESCs into cardiomyocytes in vitro is an excellent and reliable model system for studying normal cardiomyocyte development in mammals, modeling cardiac diseases, and for use in drug screening. Mouse ESC differentiation still provides relevant biological information about cardiac development. However, the current methods for efficiently differentiating ESCs into cardiomyocytes are limiting. Here, we describe the "WNT Switch" method to efficiently commit mouse ESCs into cardiomyocytes using the small molecule WNT signaling modulators CHIR99021 and XAV939 in vitro. This method significantly improves the yield of beating cardiomyocytes, reduces number of treatments, and is less laborious.

Characteristics of Vitamin A Deficiency Retinopathy at a Tertiary Referral Center in the United States.

PURPOSE: To explore the risk factors and fundus imaging features of vitamin A deficiency retinopathy (VADR) in an academic tertiary referral center in Atlanta, GA, United States, and to propose guidance regarding diagnostic workup and management of affected patients. DESIGN: Single-center retrospective case series. SUBJECTS: Nine patients seen between 2015 and 2021 at the Emory Eye Center diagnosed with VADR. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Baseline serum retinol level, Snellen visual acuity, multimodal fundus imaging findings, and electroretinography findings. RESULTS: Nine patients, 4 (44.4%) female, with a median (range) age of 68 (50-75) years were identified. The most common underlying etiologies for vitamin A deficiency included history of gastrointestinal surgery (55.6%), liver disease (44.4%), and nutritional depletion due to low-quality diet (44.4%). Only 1 (11.1%) patient had a history of bariatric surgery. Four (44.4%) patients were on some form of vitamin A supplementation before the diagnosis of VADR. Median (range) serum retinol level was 0.06 (< 0.06-0.19) mg/L. All patients had macular subretinal hyperreflective deposits resembling subretinal drusenoid deposits, although in some cases, these were scant and sparsely distributed. Six eyes of 3 patients with longstanding deficiency had defects in the external limiting membrane (ELM). Three of these eyes additionally had macular areas of complete retinal pigment epithelium and outer retinal atrophy (cRORA). Full-field electroretinography demonstrated severe rod dysfunction and mild to moderate cone system dysfunction. Many findings of VADR were reversible with vitamin A repletion. However, all eyes with ELM defects or cRORA had persistence or continued growth of these lesions. CONCLUSION: Vitamin A deficiency retinopathy is uncommon in the developed world. However, given that early intervention can lead to dramatic visual improvement and avoid potentially permanent retinal damage, retina specialists should be familiar with its clinical presentation. The presence of nyctalopia and subretinal hyperreflective deposits in a patient with a history of gastrointestinal surgery, liver disease, and/or poor diet can be suggestive of this diagnosis, even in the presence of ongoing vitamin A supplementation. Vitamin A supplementation can vary in route and dosage and can be tailored to the individual with serial testing of serum retinol. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

DHA Shortage Causes the Early Degeneration of Photoreceptors and RPE in Mice With Peroxisomal ß-Oxidation Deficiency.

Purpose: Patients deficient in peroxisomal ß-oxidation, which is essential for the synthesis of docosahexaenoic acid (DHA, C22:6n-3) and breakdown of very-long-chain polyunsaturated fatty acids (VLC-PUFAs), both important components of photoreceptor outer segments, develop retinopathy present with retinopathy. The representative mouse model lacking the central enzyme of this pathway, multifunctional protein 2 (Mfp2-/-), also show early-onset retinal decay and cell-autonomous retinal pigment epithelium (RPE) degeneration, accompanied by reduced plasma and retinal DHA levels. In this study, we investigated whether DHA supplementation can rescue the retinal degeneration of Mfp2-/- mice. Methods: Mfp2+/- breeding pairs and their offspring were fed a 0.12% DHA or control diet during gestation and lactation and until sacrifice. Offspring were analyzed for retinal function via electroretinograms and for lipid composition of neural retina and plasma with lipidome analysis and gas chromatography, respectively, and histologically using retinal sections and RPE flatmounts at the ages of 4, 8, and 16 weeks. Results: DHA supplementation to Mfp2-/- mice restored retinal DHA levels and prevented photoreceptor shortening, death, and impaired functioning until 8 weeks. In addition, rescue of retinal DHA levels temporarily improved the ability of the RPE to phagocytose outer segments and delayed the RPE dedifferentiation. However, despite the initial rescue of retinal integrity, DHA supplementation could not prevent retinal degeneration at 16 weeks. Conclusions: We reveal that the shortage of a systemic supply of DHA is pivotal for the early retinal degeneration in Mfp2-/- mice. Furthermore, we report that adequate retinal DHA levels are essential not only for photoreceptors but also for RPE homeostasis.

Three Major Causes of Metabolic Retinal Degenerations and Three Ways to Avoid Them.

An imbalance of homeostasis in the retina leads to neuron loss and this eventually results in a deterioration of vision. If the stress threshold is exceeded, different protective/survival mechanisms are activated. Numerous key molecular actors contribute to prevalent metabolically induced retinal diseases-the three major challenges are age-related alterations, diabetic retinopathy and glaucoma. These diseases have complex dysregulation of glucose-, lipid-, amino acid or purine metabolism. In this review, we summarize current knowledge on possible ways of preventing or circumventing retinal degeneration by available methods. We intend to provide a unified background, common prevention and treatment rationale for these disorders and identify the mechanisms through which these actions protect the retina. We suggest a role for herbal medicines, internal neuroprotective substances and synthetic drugs targeting four processes: parainflammation and/or glial cell activation, ischemia and related reactive oxygen species and vascular endothelial growth factor accumulation, apoptosis and/or autophagy of nerve cells and an elevation of ocular perfusion pressure and/or intraocular pressure. We conclude that in order to achieve substantial preventive or therapeutic effects, at least two of the mentioned pathways should be targeted synergistically. A repositioning of some drugs is considered to use them for the cure of the other related conditions.

Combination of Lactobacillus fermentum NS9 and aronia anthocyanidin extract alleviates sodium iodate-induced retina degeneration.

It is important to explore the effective approaches to prevent dry age-related macular degeneration (AMD). In this study, significantly decreased full-field electroretinograms wave amplitudes and disordered retina structures were detected in rat retinas of sodium iodate induced dry AMD model. Six a- and b-wave amplitudes and the antioxidant activities were significantly increased, and the outer nuclear layer thickness was significantly improved in the rat retinas treated with the combination of Lactobacillus fermentum NS9 (LF) and aronia anthocyanidin extract (AAE) compared with the model. The effects were much better than the treatment with AAE alone. The proteomics analysis showed the expressions of α-, ß- and γ-crystallins were increased by 3-8 folds in AAE treated alone and by 6-11 folds in AAE + LF treatment compared with the model, which was further confirmed by immuno-blotting analysis. Analysis of gut microbial composition indicated that higher abundance of the genus Parasutterella and species P. excrementihominis was found in the AAE + LF treatment compared with the other groups. The results indicated that the combined treatment of AAE + LF is a potential way to prevent the retina degeneration which is significantly better than the AAE treated alone.

Bujing Yishi tablets alleviate photoreceptor cells death via the P2X7R/CX3CL1/CX3CR1 pathway in Retinitis Pigmentosa rats.

BACKGROUND: Retinitis pigmentosa (RP) refers to a group of progressive photoreceptor degenerative diseases. The activation of microglia has been reported to play an important role in the photoreceptor degeneration in RP retinal. Bujing Yishi tablets (BJYS), a Chinese herbal medicine, has been used to treat retinal diseases in China with desirable effect in improving visual function. However, the mechanisms underlying the efficacy of BJYS treatment in RP are not yet fully understood. PURPOSE: Based on the preliminary experiments, this study aimed to investigate the therapeutic mechanism involved in treating N-Methyl-N-Nitrosourea (MNU)-induced retinal degeneration of RP with BJYS. METHODS: To explore the efficacy of BJYS, a rat experimental RP model was established through intraperitoneal injection of MNU (50 mg/kg). Two experiment was carried out. After the treatment, we conducted H&E, TUNEL, retinal cytokine levels and IBA-1 expression in microglia to confirm the impact on RP model. The specific mechanism of action of BJYS tablet was assessed by western blot, real-time polymerase chain reaction (RT-PCR), and immunofluorescence to determine the mRNA and protein expression levels involved in clarifying the effectiveness of BJYS exerted through P2X7R/CX3CL1/CX3CR1 pathway. RESULTS: Significant alleviation of retinal morphological structure and photoreceptor degeneration by BJYS treatment was observed in the retinal of MNU-induced RP rats, BJYS prevented the reduction of ONL thickness and decreased the level of apoptotic cells in ONL. It also inhibited microglia overactivation and reduced retinal levels of IL-1ß, IL-6, TNF-α. In addition, BJYS decreased the protein expression and mRNA expression of P2X7, CX3CL1 and CX3CR1 and reduced the phosphorylation of p38 MAPK. CONCLUSION: In summary, this study suggested that BJYS treatment could alleviate photoreceptors degeneration of RP by inhibiting microglia overactivation and inflammation through the P2X7R/CX3CL1/CX3CR1 pathway. These effects suggest that BJYS tablets may serve as a promising oral therapeutic agent for RP.

Combined drug triads for synergic neuroprotection in retinal degeneration.

This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson's disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.

Cross-modal activation of the primary visual cortex by auditory stimulation in RCS rats: considerations in visual prosthesis.

An important brain re-wiring, the so-called cross-modal plasticity, occurs during progression of retinal degenerative diseases to compensate for lack of visual input. The visual cortex does not go 'unused', instead it is devoted to processing other sensory modalities. In this study we recorded, in the visual cortex, visual- and auditory-evoked potentials in an anesthetized murine model of retinal degeneration. The latency to the first peak of the recorded local field potentials was used to assess the speed of the response. Visual responses occurred significantly faster in the control group. Conversely, auditory responses appeared significantly faster in animals with retinal degeneration. This suggests the compensatory neural rewiring is optimizing the performance of other sensory modalities, hearing in this case. This phenomenon may play an important role in visual neuro-rehabilitation. Whether or not it can promote or deter the interpretation of artificially encoded neural signals from a visual prosthesis remains to be studied.

Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.

Retinal degeneration is the major and principal cause behind many incurable blindness diseases. Several studies indicated the neuroprotective effect of Curcuma longa in eye pathologies, specifically retinopathy. However, the molecular mechanism behind its effect has not been completely elucidated. Using an ex vivo model of retinal degeneration obtained from an ex vivo optic nerve cut (ONC), we demonstrated that Curcuma extract (Cur) exerted a neuroprotective effect. Importantly, Cur was able to modulate apoptosis and MAPK signaling pathway activation and prevent retinal ganglion cell (RGC) loss. Other well-known neuroprotective pharmacological tools, including memantine (Mem), citicoline (Cit), and ginkgolic acid (GA), were used to compare the potential mechanisms of Cur. The antioxidant activity of retinas treated with Cur following optic nerve cut was significantly higher than control, but Cur failed to change the retina glutamate content. Considering the antioxidant effect of Cur and taking advantage of our recent findings on the crosstalk between oxidative stress and post-translational protein modifiers, in particular, small ubiquitin-related modifier (SUMO), we were interested in exploring the effect of Cur on SUMOylation. We found that Cur significantly prevented the increase of protein SUMOylation, confirming our previous in vitro data indicating the cytoprotective effect of curcumin through modulating the oxidative stress and SUMO-JNK axis. Altogether, these results suggest that Curcuma protects the retina from degeneration via antioxidant activity and targets SUMOylation. Therefore, it might be considered for the combination therapy with other neuroprotective agents with different mechanisms in preclinical studies on retinal degeneration.

Branched Chain Amino Acids Promote ATP Production Via Translocation of Glucose Transporters.

Purpose: We have previously shown that maintenance of ATP levels is a promising strategy for preventing neuronal cell death, and that branched chain amino acids (BCAAs) enhanced cellular ATP levels in cultured cells and antagonized cell death. BCAAs attenuated photoreceptor degeneration and retinal ganglion cell death in rodent models of retinal degeneration or glaucoma. This study aimed to elucidate the mechanisms through which BCAAs enhance ATP production. Methods: Intracellular ATP concentration was measured in HeLa cells under glycolysis and citric acid cycle inhibited conditions. Next, glucose uptake was quantified in HeLa cells and in 661W retinal photoreceptor-derived cells under glycolysis inhibition, endoplasmic reticulum stress, and glucose transporters (GLUTs) inhibited conditions, by measuring the fluorescence of fluorescently labeled deoxy-glucose analog using flow cytometry. Then, the intracellular behavior of GLUT1 and GLUT3 were observed in HeLa or 661W cells transfected with enhanced green fluorescent protein-GLUTs. Results: BCAAs recovered intracellular ATP levels during glycolysis inhibition and during citric acid cycle inhibition. BCAAs significantly increased glucose uptake and recovered decreased glucose uptake induced by endoplasmic reticulum stress or glycolysis inhibition. However, BCAAs were unable to increase intracellular ATP levels or glucose uptake when GLUTs were inhibited. Fluorescence microscopy revealed that supplementation of BCAAs enhanced the translocation of GLUTs proteins to the plasma membrane over time. Conclusions: BCAAs increase ATP production by promoting glucose uptake through promotion of glucose transporters translocation to the plasma membrane. These results may help expand the clinical application of BCAAs in retinal neurodegenerative diseases, such as glaucoma and retinal degeneration.

Retinal Toxicity Induced by Chemical Agents.

Vision is an important sense for humans, and visual impairment/blindness has a huge impact in daily life. The retina is a nervous tissue that is essential for visual processing since it possesses light sensors (photoreceptors) and performs a pre-processing of visual information. Thus, retinal cell dysfunction or degeneration affects visual ability and several general aspects of the day-to-day of a person's lives. The retina has a blood-retinal barrier, which protects the tissue from a wide range of molecules or microorganisms. However, several agents, coming from systemic pathways, reach the retina and influence its function and survival. Pesticides are still used worldwide for agriculture, contaminating food with substances that could reach the retina. Natural products have also been used for therapeutic purposes and are another group of substances that can get to the retina. Finally, a wide number of medicines administered for different diseases can also affect the retina. The present review aimed to gather recent information about the hazard of these products to the retina, which could be used to encourage the search for more healthy, suitable, or less risky agents.

Envisioning the development of a CRISPR-Cas mediated base editing strategy for a patient with a novel pathogenic CRB1 single nucleotide variant.

BACKGROUND: Inherited retinal degeneration (IRD) associated with mutations in the Crumbs homolog 1 (CRB1) gene is associated with a severe, early-onset retinal degeneration for which no therapy currently exists. Base editing, with its capability to precisely catalyse permanent nucleobase conversion in a programmable manner, represents a novel therapeutic approach to targeting this autosomal recessive IRD, for which a gene supplementation is challenging due to the need to target three different retinal CRB1 isoforms. PURPOSE: To report and classify a novel CRB1 variant and envision a possible therapeutic approach in form of base editing. METHODS: Case report. RESULTS: A 16-year-old male patient with a clinical diagnosis of early-onset retinitis pigmentosa (RP) and characteristic clinical findings of retinal thickening and coarse lamination was seen at the Oxford Eye Hospital. He was found to be compound heterozygous for two CRB1 variants: a novel pathogenic nonsense variant in exon 9, c.2885T>A (p.Leu962Ter), and a likely pathogenic missense change in exon 6, c.2056C>T (p.Arg686Cys). While a base editing strategy for c.2885T>A would encompass a CRISPR-pass mediated "read-through" of the premature stop codon, the resulting missense changes were predicted to be "possibly damaging" in in-silico analysis. On the other hand, the transversion missense change, c.2056C>T, is amenable to transition editing with an adenine base editor (ABE) fused to a SaCas9-KKH with a negligible chance of bystander edits due to an absence of additional Adenines (As) in the editing window. CONCLUSIONS: This case report records a novel pathogenic nonsense variant in CRB1 and gives an example of thinking about a base editing strategy for a patient compound heterozygous for CRB1 variants.

The visual cortical responses to sinusoidal transcorneal electrical stimulation.

Retinal stimulation has become a widely utilized approach to restore visual function for individuals with retinal degenerative diseases. Although the rectangular electrical pulse is the primary stimulus waveform used in retinal neuromodulation, it remains unclear whether alternate waveforms may be more effective. Here, we used the optical intrinsic signal imaging system to assess the responses of cats' visual cortex to sinusoidal electrical stimulation through contact lens electrode, analyzing the response to various stimulus parameters (frequency, intensity, pulse width). A comparison between sinusoidal and rectangular stimulus waveform was also investigated. The results indicated that the optimal stimulation frequency for sinusoidal electrical stimulation was approximately 20 Hz, supporting the hypothesis that low-frequency electrostimulation induces more responsiveness in retinal neurons than high-frequency electrostimulation in case of sinusoidal stimulation. We also demonstrated that for low-frequency retinal neuromodulation, sinusoidal pulses are more effective than rectangular ones. In addition, we found that compared to current intensity, the effect of the sinusoidal pulse width on cortical responses was more prominent. These results suggested that sinusoidal electrical stimulation may provide a promising strategy for improved retinal neuromodulation in clinical settings.

Long-term vitamin A supplementation in a preclinical mouse model for RhoD190N-associated retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient's case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

The possible alleviating effect of garlic supplement on the neural retina in a rat model of hypercholesterolemia: a histological and immunohistochemical study.

The purpose of this work was to prove that oxidative stress is the main mechanism responsible for retinal neurodegenerative changes, subsequent apoptosis, and inflammatory cytokine release in rats fed with a high cholesterol diet (HCD) and determine the role of garlic in alleviating these changes. Forty rats were equally divided into four groups: control, garlic-treated (positive control), HCD, and HCD + garlic-treated (HCD + G). By the end of the experiment (24 weeks) blood samples were collected for assessment of serum lipid profile, oxidative stress parameters, and plasma levels of IL-6 and TNF-α. Both eyes of the rats were enucleated; one was used for light microscopic examination and the other for electron microscopic examination. There was a significant increase in the levels of serum lipids, oxidative stress parameters, IL-6 and TNF-α, and area of expression of caspase-3 in the HCD group compared to both the control and HCD + G groups. Histological examination revealed degenerative changes in all layers of the neural retina in the HCD group. Garlic administration resulted in a significant improvement in the biochemical, immunohistochemical, and histological characteristics of hypercholesterolemic rats. These findings support the hypotheses that garlic has strong antioxidant, anti-apoptotic, and anti-inflammatory properties. Garlic ameliorates the neurodegenerative changes in the neural retina of hypercholesteremic rats.

Effect of Lecithin-Bound Iodine Treatment on Inherited Retinal Degeneration in Mice.

Purpose: Although lecithin-bound iodine (LBI) has been administered orally for retinal diseases, a lack of clinical studies and obscure action mechanism of LBI hinder its large-scale prescription. LBI treatment suppresses chemokine (C-C motif) ligand 2 (CCL2) secretion from retinal pigment epithelial cells in vitro. Herein, we assessed the in vivo effect of LBI treatment on retinal degeneration (RD) in mice. Methods: Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice-a model for RD-demonstrate fluorescein-labeled microglia/macrophage to facilitate visualization of CX3CR1-green fluorescent protein (GFP) and CCR2-red fluorescent protein (RFP). An LBI-containing mouse diet was provided to Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice ad libitum from postnatal day (POD) 28. CX3CR1-GFP and CCR2-RFP expression was assessed at POD 56 using retinal sectioning and flat mounting. RD severity was assessed at POD 84. Retinal RNA was extracted from the mice of each group to measure chemokine expression. Electroretinography was performed to assess retinal function. Results: CCR2-RFP expression in the retina and retinal pigment epithelial cells was suppressed by LBI treatment compared with that in the control at POD 56. The number of outer nuclear layer nuclei was higher in the group fed with LBI-containing diet than in the control mice at POD 84. Ccl2 and Ccr2 RNA expression was suppressed by LBI intake. Electroretinography showed the LBI-treated group to have a high b-wave amplitude compared with the control group. Conclusions: Suppressing CCR2-RFP-positive macrophage invasion into the retina and CCL2 and CCR2 expression is a potential mechanism underlying LBI-mediated attenuation of RD. Translational Relevance: Life-long LBI administration may become a candidate for treating RD.

Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases.

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

Involvement of endoplasmic reticulum stress in rotenone-induced leber hereditary optic neuropathy model and the discovery of new therapeutic agents.

Leber hereditary optic neuropathy (LHON) is caused by mitochondrial DNA mutations and is the most common inherited mitochondrial disease. It is responsible for central vision loss in young adulthood. However, the precise mechanisms of onset are unknown. This study aimed to elucidate the mechanisms underlying LHON pathology and to discover new therapeutic agents. First, we assessed whether rotenone, a mitochondrial complex Ⅰ inhibitor, induced retinal degeneration such as that in LHON in a mouse model. Rotenone decreased the thickness of the inner retina and increased the expression levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and immunoglobulin heavy-chain binding protein (BiP). Second, we assessed whether rotenone reproduces LHON pathologies on RGC-5, a neural progenitor cell derived from the retina. Rotenone increased the cell death rate, ROS production and the expression levels of ER stress markers. During chemical compounds screening, we used anti-oxidative compounds, ER stress inhibitors and anti-inflammatory compounds in a rotenone-induced in vitro model. We found that SUN N8075, an ER stress inhibitor, reduced mitochondrial ROS production and improved the mitochondrial membrane potential. Consequently, the ER stress response is strongly related to the pathologies of LHON, and ER stress inhibitors may have a protective effect against LHON.

Red Light Irradiation In Vivo Upregulates DJ-1 in the Retinal Ganglion Cell Layer and Protects against Axotomy-Related Dendritic Pruning.

Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Photobiomodulation (PBM) with red light provided neuroprotection to RGCs when administered ex vivo to wild-type retinal explants. In the current study, we used aged (13-15-month-old) wild-type and heterozygous B6;C3-Opa1Q285STOP (Opa1+/-) mice, a model of ADOA exhibiting RGC dendropathy. These mice were pre-treated with 4 J/cm2 of 670 nm light for five consecutive days before the eyes were enucleated and the retinas flat-mounted into explant cultures for 0-, 8- or 16-h ex vivo. RGCs were imaged by confocal microscopy, and their dendritic architecture was quantified by Sholl analysis. In vivo 670 nm light pretreatment inhibited the RGC dendropathy observed in untreated wild-type retinas over 16 h ex vivo and inhibited dendropathy in ON-center RGCs in wild-type but not Opa1+/- retinas. Immunohistochemistry revealed that aged Opa1+/- RGCs exhibited increased nitrosative damage alongside significantly lower activation of NF-κB and upregulation of DJ-1. PBM restored NF-κB activation in Opa1+/- RGCs and enhanced DJ-1 expression in both genotypes, indicating a potential molecular mechanism priming the retina to resist future oxidative insult. These data support the potential of PBM as a treatment for diseases involving RGC degeneration.