Case of persistent corneal epithelial damage after cataract surgery leading to diagnosis of vitamin A deficiency.

PURPOSE: To report our findings of reduced full-field electroretinograms (ff-ERGs) and abnormal optical coherence tomographic (OCT) images in a patient with poor visual acuity after cataract surgery who was eventually diagnosed with vitamin A deficiency (VAD). METHODS: This was a clinical study of a patient who complained of blurred vision after cataract surgery. To determine the cause of the reduced vision, we recorded full-field electroretinograms (ff-ERGs) to determine the scotopic and photopic status of the retina. We also performed optical coherence tomography to assess the changes in the retinal structure. Serological tests were performed. RESULTS: A 74-year-old man presented with persistent corneal epithelial damages and reduced vision that developed after conventional cataract surgery. OCT showed an interrupted ellipsoid zone, and fundus autofluorescence (FAF) showed a severe hypofluorescence in the retina of the left eye. The scotopic ff-ERGs were severely reduced, and the photopic ff-ERGs were mildly reduced. Serological examinations revealed a vitamin A concentration < 7 IU/dL (normal, 97-316 IU/dL). Based on these findings, we diagnosed the patient with VAD and started treatment with oral vitamin A supplements. After three months, his visual acuity, ff-ERGs, and OCT findings recovered to normal levels. The amplitudes and implicit times of the RETeval flicker ERGs increased to be within the normal range, and the hypofluorescence of the left eye disappeared. The length of the photoreceptor outer segments increased after the vitamin A supplementation. CONCLUSION: Our findings indicate that the ERGs are helpful for diagnosing patients with VAD associated with persistent corneal epithelial damages.

Diffuse retinal dysfunction following immune reconstitution uveitis in patients with prior cytomegalovirus retinitis: a novel observation.

PURPOSE: To report continuing diffuse retinal dysfunction following resolution of immune reconstitution uveitis (IRU) in patients with cytomegalovirus retinitis (CMVR). METHODS: Retrospective case series describing two patients with IRU following CMVR who underwent serial fundus photography and macular optical coherence tomography. One patient had serial electrophysiology. RESULTS: Both patients had CMVR successfully treated with antiviral medication. The affected eyes later developed IRU that resolved with steroids. However, following resolution, chronic retinal damage was evidenced by ellipsoid line loss in one case and gradual optic disc cupping in the other. Electrophysiology in both cases revealed generalized retinal dysfunction worse in the eye with more severe IRU and demonstrated objectively the efficacy of treatment intervention in the patient with serial recordings. CONCLUSIONS: Patients with IRU following CMV retinitis may have continuing diffuse retinal dysfunction despite apparent recovery and normal visual acuity. An aggressive approach to inflammation control may be warranted in such patients.

One-Year Outcomes of Oral Treatment With Alga Capsules Containing Low Levels of 9-cis-ß-Carotene in RDH5-Related Fundus Albipunctatus.

PURPOSE: This study aimed to clarify the effect of 1-year oral treatment with 9-cis-ß-carotene-rich alga Dunaliella bardawil (Dunaliella supplementation) using full-field electroretinography (ERG) in patients with RDH5-related fundus albipunctatus (FAP). DESIGN: Prospective, interventional case series. PARTICIPANTS: The study included 12 patients (23 eyes) with RDH5-related FAP. METHODS: Twelve patients (23 eyes) with RDH5-related FAP received Dunaliella supplementation (total daily dose of ß-carotene was 74.0 mg, comprising 28.4 mg 9-cis-ß-carotene and 45.6 mg all-trans-ß-carotene at a ratio of 1:1.6) for 1 year and underwent ophthalmic examinations, including full-field ERG at baseline, 3 months, and 1 year after the initial treatment. MAIN OUTCOME MEASURES: The main outcome was changes in the amplitudes of responses of full-field ERG before and after treatment. A linear mixed-effects model was used to evaluate the adjusted mean difference between the amplitude of each response pretreatment and posttreatment. RESULTS: Prolonged dark adaptation (DA) responses at 3 months revealed a significant impairment in the b-wave of DA 0.01 (adjusted mean difference, -34.7, 95% CI, -66.8 to -2.73, P = .041) and a-wave of DA 3.0 (-29.0, 95% CI, -50.6 to -7.41, P = .013) and DA 10.0 (-40.4, 95% CI, -67.8 to -13.0, P = .007), which were also observed at 1 year. Additionally, prolonged DA and light adaptation (LA) responses revealed statistically significant impairment at 1 year in the b-wave of DA 3.0 (-43.8, 95% CI, -82.9 to -4.78, P = .035), DA 10.0 (-59.7, 95% CI, -101.8 to -17.61, P = .009), LA 3.0 (-7.31, 95% CI, -13.6 to -1.04, P = .029), and LA 3.0 flicker (-7.53, 95% CI, -12.7 to -2.34, P = .007). CONCLUSIONS: Our study results suggest that Dunaliella supplementation comprising low levels of 9-cis-ß-carotene compared with those reported in a previous study (1:1 ratio) adversely affects ERG amplitudes in patients with RDH5-related FAP.

Electrophysiological effects of hyperbaric oxygen treatment on the healthy retina.

PURPOSE: The study aimed to investigate the electrophysiological effects of hyperbaric oxygen treatment (HBOT) on the retina after ten sessions in healthy eyes. METHODS: This prospective, interventional study evaluated forty eyes of twenty patients who were treated with HBOT of ten sessions with the diagnosis of an extraocular health problem. All patients underwent a complete ophthalmologic examination, including assessments of best-corrected visual acuity (BCVA), slit-lamp and pupil-dilated fundus examinations, full-field electroretinography (ffERG) measurements before and after HBOT within 24 h of the 10th session. The ffERG was recorded according to the International Society for Clinical Electrophysiology of Vision protocol using the RETI-port system. RESULTS: The mean age of patients was 40.5 years ranging from 20 to 59 years. Thirteen patients were administered HBOT for avascular necrosis, six patients for sudden hearing loss, and one patient for chronic osteomyelitis of the vertebra. BCVA acuity was 20/20 in all eyes. The mean spherical refractive was 0.56 dioptre (D), and the mean cylindrical refractive error was 0.75 D. Dark-adapted b-wave amplitude in 3.0 ERG was the only variable for the b-wave that showed a statistically significant decrease (p = 0.017). The amplitude of the a-waves in dark-adapted 10.0 ERG and light-adapted 3.0 ERG reduced significantly (p = 0.024, p = 0.025). The amplitude of N 1-P 1 in light-adapted 30 Hz Flicker ERG also demonstrated a statistically significant decrease (p = 0.011). Implicit times did not differ significantly in any of the ffERG data (p > 0.05). CONCLUSIONS: HBOT caused the deterioration of a-wave and b-wave amplitudes in ffERG after ten treatment sessions. The results showed that photoreceptors were adversely affected in the short term after HBOT treatment.

Correlation between the Serum Concentration of Vitamin A and Disease Severity in Patients Carrying p.G90D in RHO, the Most Frequent Gene Associated with Dominant Retinitis Pigmentosa: Implications for Therapy with Vitamin A.

The pathogenic variant p.G90D in RHO is believed to be responsible for a spectrum of phenotypes, including congenital stationary blindness (for the purpose of this study termed night blindness without degeneration; NBWD), Sector RP, Pericentral RP, and Classic RP. We present a correlation between the serum concentration of vitamin A and disease severity in patients with this variant. This prospective study involved 30 patients from 7 families (17 male; median age 46 years, range 8−73). Full ophthalmological examination including visual acuity, Goldmann perimetry, slit-lamp exam, optical coherence tomography, fundus autofluorescence, and electrophysiology was performed to determine the presenting phenotype. The serum concentration of vitamin A was determined from a fasting blood sample taken on the day of the exam, where it was found that 23.3% (7/30) of patients had NBWD, 13.3% (4/30) had Sector RP, 3.3% (1/30) had Pericentral RP, and 60% (18/30) had Classic RP. Multiple logistic regression revealed a significantly higher probability of having a milder phenotype (NBWD or Sector RP) in association with younger age (p < 0.05) and a higher concentration of vitamin A (p < 0.05). We hypothesize that vitamin A in its 11-cis-retinal form plays a role in stabilizing the constitutively active p.G90D rhodopsin and its supplementation could be a potential treatment strategy for p.G90D RHO patients.

Bilateral compressive optic neuropathy and outer retinopathy due to optic canal hyperostosis in a child with isolated vitamin a deficiency.

PURPOSE: Vitamin A plays a crucial role in rod phototransduction, with deficient levels manifesting as night blindness. Animal models have demonstrated bone dysplasia in the setting of hypovitaminosis A. We present a rare case of bony overgrowth leading to bilateral compressive optic neuropathy, combined with outer retinopathy, in a paediatric patient secondary to isolated vitamin A deficiency. METHODS: A single case report was conducted from Toronto, Canada. RESULTS: A 12-year-old boy with known autism spectrum disorder presented with a 9-month history of progressive painless vision loss. Vision was 20/300 and hand motion in the right and left eye, respectively. Fundus photography demonstrated bilateral optic atrophy and yellow lesions notably in the right eye far periphery. Optical coherence tomography (OCT) imaging demonstrated thinning of the retinal nerve fibre layer, alterations in the ellipsoid zone, as well as retinal pigment epithelium deposits. Computed tomography imaging demonstrated sphenoid bone thickening with narrow optic canals and moderate optic atrophy bilaterally. Full-field electroretinogram (ERG) demonstrated mildly reduced dark adapted (DA) 0.01 b-wave amplitudes and electronegative configuration of DA 3.0 and DA 10.0 ERG; the light adapted ERGs were normal. The patient was treated with pulse vitamin A therapy. Subsequently, the DA ERG normalized, outer retinal changes reversed and vision stabilised; no surgical intervention was conducted. CONCLUSION: This case represents a rare presentation of compressive optic neuropathy with concomitant outer retinopathy secondary to isolated vitamin A deficiency. Despite improvement in outer retinal integrity on OCT imaging and ERG testing results following vitamin A supplementation, no functional improvement was obtained due to severe optic atrophy.

Vitamin A deficiency and the retinal "double carrot" sign with optical coherence tomography.

BACKGROUND: Spectral-domain optical coherence tomography (SD-OCT) and full-field electroretinography (ERG) allow retinal assessment with vitamin A deficiency (VAD). Using SD-OCT, this study aimed to characterize and follow a novel retinal abnormality in patients with VAD and intramuscular supplementation. METHODS: Patients with VAD were retrospectively reviewed, including SD-OCT and electroretinography. RESULTS: Three patients had VAD following bariatric or colon surgery and varying supplementation. All had nyctalopia, extinguished scotopic rod-specific function with ERG, and decreased serum vitamin A. None demonstrated surface abnormalities. All received intramuscular vitamin A with subjective resolution of symptoms. On SD-OCT, four of six eyes exhibited homogenous foveal hyperreflectivity anterior to retinal pigment epithelium-Bruch complex, reminiscent of a "double carrot", which improved following supplementation. ERG findings demonstrated improved scotopic rod-specific function in all cases; however, photopic function remained diminished in two cases. CONCLUSIONS: Structural improvement of the proposed "double carrot" sign occurs soon after vitamin A supplementation. While scotopic function improves rapidly following supplementation, cone function recovers more slowly. Therefore, foveal changes such as the "double carrot" sign suggest that structural recovery of cones precedes functional recovery.

Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q10 deficiency.

PURPOSE: To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS: Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS: An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS: Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.

Outcomes of transcorneal electrical stimulation therapy in the early stages of retinitis pigmentosa.

BACKGROUND: To investigate the effect of transcorneal electrical stimulation (TES) therapy in patients with retinitis pigmentosa (RP). METHODS: We performed TES therapy in 21 patients with RP in 12 sessions with 1-week intervals. The following parameters obtained before and after the TES therapy were compared statistically; the best corrected visual acuity (BCVA, logMAR), Ishihara color vision level, multifocal electroretinography (mf-ERG) response, automated visual field (VF) outcome, and the 25-item low vision quality-of-life (LVQOL) questionnaire points. RESULTS: The mean age of patients (6 females; 15 males) was 31.67 ± 9.80 years (20-50 years). While increases in BCVA level, color vision level, mf-ERG response in p1 amplitude of ring 1, and LVQOL questionnaire points were statistically significant, changes in VF test and other mf-ERG responses were not. Twenty of the patients (95.24%) stated that they were satisfied with the TES therapy. No considerable side effect was observed in any patient due to the therapy. DISCUSSION: The TES therapy may be an effective and safe treatment modality in slowing the RP progression, especially in the early stages of the disease. Longer-term follow-ups in larger patient populations are warranted.

Documentation of recovery from vitamin A deficiency-related retinopathy via multimodal imaging and electroretinogram testing.

PURPOSE: To describe vitamin A deficiency using multimodal functional visual assessments and imaging. METHODS/CASE: A 50-year-old female with past medical history significant for Roux-en-Y gastric bypass surgery complained of nyctalopia and "yellowing" of vision. RESULTS: Vitamin A levels were noted to be < 0.06 mg/L (normal 0.3-0.12 mg/L). Fundus examination was notable for peripheral yellow punctate lesions, superior arcuate defects on HVF 30-2 testing, an indistinct ellipsoid zone on SD-OCT, and absent rod responses and severely reduced amplitudes for the cone photoreceptors on full-field ERG. These findings resolved with initiation of parenteral vitamin A supplementation. CONCLUSION: This report documents an example of vitamin A deficiency in the developed world. We aim to provide a comprehensive description of clinical examination and multimodal imaging findings before and after vitamin supplementation for vitamin A deficiency.

Serial ERG monitoring of response to therapy in vitamin A deficiency related night blindness.

Two male patients with known systemic disorders who presented with complaints of nyctalopia underwent a complete ophthalmic examination including electrophysiological evaluation and serum vitamin A (retinol) levels. A significant vitamin A deficiency was detected, supplementation started and repeat electroretinogram (ERG) testing was carried out to monitor the timeline of recovery. Restoration of rod and generalised cone function was rapid within the first week of receiving treatment and near normal recovery was seen after 1 month of supplementation. Serial monitoring of ERG changes in vitamin A deficiency (VAD) associated night blindness plays an important role to demonstrate functional recovery post-treatment. The different effects of VAD on rod and cone function, and their rate of recovery, may reflect differences in the visual cycle between the two photoreceptors. We report the serial ERG changes in VAD related night blindness secondary to intestinal lipofuscinosis and liver cirrhosis in two patients.

Rs1h-/y exon 3-del rat model of X-linked retinoschisis with early onset and rapid phenotype is rescued by RS1 supplementation.

Animal models of X-linked juvenile retinoschisis (XLRS) are valuable tools for understanding basic biochemical function of retinoschisin (RS1) protein and to investigate outcomes of preclinical efficacy and toxicity studies. In order to work with an eye larger than mouse, we generated and characterized an Rs1h-/y knockout rat model created by removing exon 3. This rat model expresses no normal RS1 protein. The model shares features of an early onset and more severe phenotype of human XLRS. The morphologic pathology includes schisis cavities at postnatal day 15 (p15), photoreceptors that are misplaced into the subretinal space and OPL, and a reduction of photoreceptor cell numbers by p21. By 6 mo age only 1-3 rows of photoreceptors nuclei remain, and the inner/outer segment layers and the OPL shows major changes. Electroretinogram recordings show functional loss with considerable reduction of both the a-wave and b-wave by p28, indicating early age loss and dysfunction of photoreceptors. The ratio of b-/a-wave amplitudes indicates impaired synaptic transmission to bipolar cells in addition. Supplementing the Rs1h-/y exon3-del retina with normal human RS1 protein using AAV8-RS1 delivery improved the retinal structure. This Rs1h-/y rat model provides a further tool to explore underlying mechanisms of XLRS pathology and to evaluate therapeutic intervention for the XLRS condition.

Retinal Temperature Determination Based on Photopic Porcine Electroretinogram.

OBJECTIVE: Subthreshold retinal laser therapy (SLT) is a treatment modality where the temperature of the retinal pigment epithelium (RPE) is briefly elevated to trigger the therapeutic benefits of sublethal heat shock. However, the temperature elevation induced by a laser exposure varies between patients due to individual differences in RPE pigmentation and choroidal perfusion. This study describes an electroretinography (ERG)-based method for controlling the temperature elevation during SLT. METHODS: The temperature dependence of the photopic ERG response kinetics were investigated both ex vivo with isolated pig retinas and in vivo with anesthetized pigs by altering the temperature of the subject and recording ERG in different temperatures. A model was created for ERG-based temperature estimation and the feasibility of the model for controlling SLT was assessed through computational simulations. RESULTS: The kinetics of the photopic in vivo flash ERG signaling accelerated between 3.6 and 4.7%/°C, depending on the strength of the stimulus. The temperature dependence was 5.0%/°C in the entire investigated range of 33 to 44°C in ex vivo ERG. The simulations showed that the method is suitable for determining the steady-state temperature elevation in SLT treatments with a sufficiently long laser exposure and large spot size, e.g., during > 30 s laser exposures with > 3 mm stimulus spot diameter. CONCLUSIONS: The described ERG-based temperature estimation model could be used to control SLT treatments such as transpupillary thermotherapy. SIGNIFICANCE: The introduced ERG-based method for controlling SLT could improve the repeatability, safety, and efficacy of the treatment of various retinal disorders.

TRANSCORNEAL ELECTRICAL STIMULATION THERAPY MAY HAVE A STABILIZATION EFFECT ON MULTIFOCAL ELECTRORETINOGRAPHY FOR PATIENTS WITH RETINITIS PIGMENTOSA.

PURPOSE: To assess the effects of transcorneal electrical stimulation (TES) on several measures of visual function in retinitis pigmentosa. METHODS: This prospective, randomized, fellow-eye-controlled study includes 30 eyes of 15 patients with retinitis pigmentosa. Each patient's eyes were randomly selected as treatment (TE) and control eye (CE), and 30 minutes/week TES was applied for 6 months. Patient evaluations were performed before and after TES, including comprehensive ophthalmological examination, visual fields, full-field and multifocal electroretinography, microperimetry, and optical coherence tomography. All parameters were compared before and after TES and between TE and CE. RESULTS: After TES, the mean signal amplitudes in multifocal electroretinography were stabilized in TE. The mean signal amplitudes in CE decreased in every ring, reaching significance in the fifth ring (847.15 ± 393.94 and 678.77 ± 282.66 nV, P = 0.039, before and after TES, respectively). The changes in the mean signal amplitudes of TE and CE were -0.38 ± 295.53 and -185.15 ± 332,62 nV in second (P = 0.046), 36.69 ± 326.4 and -143.38 ± 317,41 nV in fourth (P = 0.028), and -17.46 ± 333.07 and -168.38 ± 297,14 nV in fifth rings (P = 0.046), respectively. The decrease in the mean signal amplitudes between 2° and 20° midperipheral retina was significantly less in TE (-33.59 ± 225,1 nV) than CE (-205.56 ± 345.1 nV) (P = 0.011). There were no significant changes in other parameters. CONCLUSION: The progression in multifocal electroretinography might be stabilized with TES. Further studies with larger sample sizes and a longer follow-up are needed to conclude that TES reduces retinitis pigmentosa progression.

A Circadian Rhythm of Visual Sensitivity in the American Lobster, Homarus americanus.

AbstractTo determine whether eyes of American lobsters (Homarus americanus) are more sensitive to light at night than during the day, electroretinograms were continuously recorded from 23 adult lobsters for at least 3 days (range: 3 to 9 days) in constant darkness. A green light-emitting diode, mounted 10 cm away from the eyes, was briefly flashed every 2 minutes to evoke the electroretinogram. The average increase in the response to a light flash, between the minimum during the subjective day and the maximum during the subjective night, was 105.6% ± 38.8%; and there was a statistically significant difference between day and night responses. This change in visual sensitivity took place while lobsters were held in constant darkness, suggesting that it was due to the influence of a circadian clock. The average period (tau) for the 10 animals that expressed significant circadian rhythms was 23.4 ± 0.8 hours. Previous studies have demonstrated that lobsters have circadian clocks that influence their locomotor activity; and the present data suggest that this is also true for their eyes, leading to an increase in their visual sensitivity at night, when they are typically most active.

Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression.

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

Depleting hypothalamic somatostatinergic neurons recapitulates diabetic phenotypes in mouse brain, bone marrow, adipose and retina.

AIMS/HYPOTHESIS: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. METHODS: The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA). RESULTS: SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice. CONCLUSIONS/INTERPRETATION: The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.

Lutein and zeaxanthin reduce A2E and iso-A2E levels and improve visual performance in Abca4-/-/Bco2-/- double knockout mice.

Accumulation of bisretinoids such as A2E and its isomer iso-A2E is thought to mediate blue light-induced oxidative damage associated with age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). We hypothesize that increasing dietary intake of the macular carotenoids lutein and zeaxanthin in individuals at risk of AMD and STGD1 can inhibit the formation of bisretinoids A2E and iso-A2E, which can potentially ameliorate macular degenerative diseases. To study the beneficial effect of macular carotenoids in a retinal degenerative diseases model, we used ATP-binding cassette, sub-family A member 4 (Abca4-/-)/ß,ß-carotene-9',10'-oxygenase 2 (Bco2-/-) double knockout (KO) mice that accumulate elevated levels of A2E and iso-A2E in the retinal pigment epithelium (RPE) and macular carotenoids in the retina. Abca4-/-/Bco2-/- and Abca4-/- mice were fed a lutein-supplemented chow, zeaxanthin-supplemented chow or placebo chow (~2.6 mg of carotenoid/mouse/day) for three months. Visual function and electroretinography (ERG) were measured after one month and three months of carotenoid supplementation. The lutein and zeaxanthin supplemented Abca4-/-/Bco2-/- mice had significantly lower levels of RPE/choroid A2E and iso-A2E compared to control mice fed with placebo chow and improved visual performance. Carotenoid supplementation in Abca4-/- mice minimally raised retinal carotenoid levels and did not show much difference in bisretinoid levels or visual function compared to the control diet group. There was a statistically significant inverse correlation between carotenoid levels in the retina and A2E and iso-A2E levels in the RPE/choroid. Supplementation with retinal carotenoids, especially zeaxanthin, effectively inhibits bisretinoid formation in a mouse model of STGD1 genetically enhanced to accumulate carotenoids in the retina. These results provide further impetus to pursue oral carotenoids as therapeutic interventions for STGD1 and AMD.

Fructus Lycii and Salvia miltiorrhiza Bunge extract alleviate retinitis pigmentosa through Nrf2/HO-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Lycii and Salvia miltiorrhiza Bunge (FS) are popular Chinese herbs for the treatment of retinitis pigmentosa (RP). AIM OF THE STUDY: This study was to evaluate protective effects of FS extract on RP and to explore whether FS extract exerts its protective effects via oxidative stress by regulating Nrf2/HO-1 signaling pathway. MATERIAL AND METHODS: FS extract were identified by UPLC chromatographic analysis. Rd10 mice as the model of RP, followed by a 4-week FS extract treatment by intragastric administration. After the animal sacrifice, histopathological examination and Scotopic electroretinography (ERG) analysis were assessed. The oxidative stress markers were determined and the expression levels of Nrf2 and HO-1 mRNA were evaluated by qRT-PCR. The expression and distribution of Nrf2 and HO-1 protein were determined by Western blot and immunohistochemistry. RESULTS: The morphological changes of Outer nuclear layer (ONL) thickness and number of the ONL were observed with a significant increased, and the functional changes of a-amplitude and b-wave amplitude were measured with a markedly increased. Treatment with FS extract remarkably increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and decreased level of malondialdehyde (MDA). Moreover, FS extract up-regulated mRNA and protein expression of Nrf2 and HO-1. CONCLUSIONS: This study indicated that FS extract can improve retinal morphology and function, which may have occurred through the regulation of the Nrf2/HO-1 pathway to inhibit the oxidative reaction.

Photoperiodic regulation of dopamine signaling regulates seasonal changes in retinal photosensitivity in mice.

At high latitudes, approximately 10% of people suffer from depression during the winter season, a phenomenon known as seasonal affective disorder (SAD). Shortened photoperiod and/or light intensity during winter season are risk factors for SAD, and bright light therapy is an effective treatment. Interestingly, reduced retinal photosensitivity along with the mood is observed in SAD patients in winter. However, the molecular basis underlying seasonal changes in retinal photosensitivity remains unclear, and pharmacological intervention is required. Here we show photoperiodic regulation of dopamine signaling and improvement of short day-attenuated photosensitivity by its pharmacological intervention in mice. Electroretinograms revealed dynamic seasonal changes in retinal photosensitivity. Transcriptome analysis identified short day-mediated suppression of the Th gene, which encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine biosynthesis. Furthermore, pharmacological intervention in dopamine signaling through activation of the cAMP signaling pathway rescued short day-attenuated photosensitivity, whereas dopamine receptor antagonists decreased photosensitivity under long-day conditions. Our results reveal molecular basis of seasonal changes in retinal photosensitivity in mammals. In addition, our findings provide important insights into the pathogenesis of SAD and offer potential therapeutic interventions.