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PURPOSE: Bioelectronic retinal prostheses that stimulate the remaining inner retinal neurons, bypassing degenerated photoreceptors, have been demonstrated to restore some vision in patients blinded by retinitis pigmentosa (RP). These implants encode luminance of the visual scene into electrical stimulation, however, leaving out chromatic information. Yet color plays an important role in visual processing when it comes to recognizing objects and orienting to the environment, especially at low spatial resolution as generated by current retinal prostheses. In this study, we tested the feasibility of partially restoring color perception in blind RP patients, with the aim to provide chromatic information as an extra visual cue. DESIGN: Case series. PARTICIPANTS: Seven subjects blinded by advanced RP and monocularly fitted with an epiretinal prosthesis. METHODS: Frequency-modulated electrical stimulation of retina was tested. Phosphene brightness was controlled by amplitude tuning, and color perception was acquired using the Red, Yellow, Green, and Blue (RYGB) hue and saturation scaling model. MAIN OUTCOME MEASURES: Brightness and color of the electrically elicited visual perception reported by the subjects. RESULTS: Within the tested parameter space, 5 of 7 subjects perceived chromatic colors along or nearby the blue-yellow axis in color space. Aggregate data obtained from 20 electrodes of the 5 subjects show that an increase of the stimulation frequency from 6 to 120 Hz shifted color perception toward blue/purple despite a significant inter-subject variation in the transition frequency. The correlation between frequency and blue-yellow perception exhibited a good level of consistency over time and spatially matched multi-color perception was possible with simultaneous stimulation of paired electrodes. No obvious correlation was found between blue sensations and array placement or status of visual impairment. CONCLUSIONS: These findings present a strategy for the generation and control of color perception along the blue-yellow axis in blind patients with RP by electrically stimulating the retina. It could transform the current prosthetic vision landscape by leading in a new direction beyond the efforts to improve the visual acuity. This study also offers new insights into the response of our visual system to electrical stimuli in the photoreceptor-less retina that warrant further mechanistic investigation.
Assuntos
Cegueira/fisiopatologia , Percepção de Cores/fisiologia , Terapia por Estimulação Elétrica , Retina/fisiopatologia , Retinose Pigmentar/terapia , Próteses Visuais , Idoso , Visão de Cores/fisiologia , Eletrodos Implantados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfenos , Células Fotorreceptoras de Vertebrados/fisiologia , Retinose Pigmentar/fisiopatologia , Limiar Sensorial/fisiologia , Acuidade VisualRESUMO
With 329 genes known to be involved in inherited retinal degenerations (IRDs), focus has shifted to generic targets for therapeutics, targets that could provide benefit irrespective of the underlying genetic condition. As one of the most energy-demanding tissues, the retina is acutely sensitive to dysfunction of its energy metabolism. Recent discoveries have shed light on the complex interconnectivity and interdependence of retinal cells on their choice metabolic pathways, highlighting a number of potential targets that could benefit cells in a mutation-independent manner. Some of the latest research on retinal metabolism and mitophagy in photoreceptors and retinal pigment epithelium is discussed, as is how these insights could potentially be used in the design of new therapies.
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Metabolismo Energético , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/fisiologia , Degeneração Retiniana , Epitélio Pigmentado da Retina/fisiologia , Humanos , MitofagiaRESUMO
Lighting based on light-emitting diodes (LEDs) not only is more energy efficient than traditional lighting, but also enables improved performance and control. The colour, intensity and distribution of light can now be controlled with unprecedented precision, enabling light to be used both as a signal for specific physiological responses in humans and plants, and as an efficient fuel for fresh food production. Here we show how a broad and improved understanding of the physiological responses to light will facilitate greater energy savings and provide health and productivity benefits that have not previously been associated with lighting.
Assuntos
Agricultura/instrumentação , Alimentos , Saúde , Iluminação/instrumentação , Iluminação/métodos , Fótons , Agricultura/métodos , Animais , Encéfalo/fisiologia , Encéfalo/efeitos da radiação , Ritmo Circadiano/efeitos da radiação , Conservação de Recursos Energéticos , Eficiência/fisiologia , Eficiência/efeitos da radiação , Olho/efeitos da radiação , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Iluminação/economia , Iluminação/história , Células Fotorreceptoras de Vertebrados/fisiologia , Células Fotorreceptoras de Vertebrados/efeitos da radiação , FototerapiaRESUMO
The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild-type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20â¯Hz; envelope frequency constantly kept at 1.2â¯Hz) and intensities (10, 20, 50⯵A) were recorded and compared with those obtained with light stimulation (1.2â¯Hz sinusoidal blue, red light). A strong correlation between the sinusoidal stimulation (electrical as well as light) and the pupillary sinusoidal response was found. The difference between the lag of electrical and light stimulation allowed the estimation of an intensity threshold for pupillary responses to transcorneal electrostimulation (mean⯱â¯SD: 30⯱â¯10⯵A (10â¯Hz); 38⯱â¯10⯵A (20â¯Hz)). A comparison between the results of the two stimulation frequencies showed a not statistically significant smaller lag for 10â¯Hz (10â¯Hz: 633⯱â¯90â¯ms; 20â¯Hz: 725⯱â¯178â¯ms; 50⯵A intensity). Analogous in vitro experiments on murine retinas indicated a selective stimulation of photoreceptors and bipolar cells (lower frequencies) and retinal ganglion cells (higher frequencies) and lower stimulation thresholds for the retinal network with sinusoidal compared to pulsatile stimulation - emphasizing that sinusoidal waveforms are well-suited to our purposes. We demonstrate that pupillary responses to sinusoidal transcorneal electrostimulation are measurable as an objective marker in healthy young subjects, even at very low stimulus intensities. By using this unique approach, we unveil the potential for an estimation of the individual intensity threshold and a selective activation of different retinal cell types in humans by varying the stimulation frequency. This technique may have broad clinical utility as well as specific relevance in the monitoring of patients with hereditary retinal disorders, especially as implemented in study protocols for novel therapies, e.g. retinal prostheses or gene therapies.
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Estimulação Elétrica , Fosfenos/fisiologia , Reflexo Pupilar/fisiologia , Retina/fisiologia , Percepção Visual/fisiologia , Adulto , Animais , Córnea/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa , Células Fotorreceptoras de Vertebrados/fisiologia , Células Bipolares da Retina/fisiologia , Células Ganglionares da Retina/fisiologiaRESUMO
BACKGROUND: A dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (AA) is critical for neonatal retinal development. Both are absent/minimal in parenteral nutrition (PN) using soy-oil emulsions ([SO] Intralipid®) traditionally used for neonatal intestinal failure. In contrast, fish-oil emulsions ([FO] Omegaven®) are enriched in DHA/AA. The aim of this study was to compare retinal function and fatty acid content in neonatal piglets fed PN with SO or FO. METHODS: Two-5-day-old piglets were randomly allocated to SO (n = 4) or FO (n = 4), provided at equivalent doses (5g/kg/d). After 14 days of PN, retinal function was assessed by electroretinography and retinas were harvested for fatty acid content analysis. Sow-fed piglets served as a reference (REF). RESULTS: Light flash-elicited stoppage of cone and rod dark-currents (a-waves) and the ensuing postsynaptic activation of cone and rod ON bipolar cells (b-waves) were comparable between SO and REF. Responses recorded from FO were subnormal (P <0.001) when compared with both SO and REF. Retinal DHA content was similar in both groups (FO, 14.59% vs SO, 12.22%; P = 0.32); while AA was lower in FO (FO, 6.01% vs SO, 8.21%; P = .001). CONCLUSION: Paradoxically, FO containing more DHA and AA did not preserve retinal function when compared with the same low dose of SO. This may be due to the reduced AA enrichment in the retina with FO treatment. Further investigation into the ideal amounts of DHA and AA for optimal neonatal retinal function is required.
Assuntos
Ácido Araquidônico/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Emulsões Gordurosas Intravenosas/química , Óleos de Peixe/química , Nutrição Parenteral , Retina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ácido Araquidônico/metabolismo , Ácido Araquidônico/farmacologia , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Emulsões , Ácidos Graxos/administração & dosagem , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Masculino , Fosfolipídeos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/citologia , Retina/fisiologia , Óleo de Soja , Suínos , TriglicerídeosRESUMO
Purpose: As an active component in wolfberry, lycium barbarum polysaccharides (LBP) are capable of protecting retinal neurons in several animal disease models. Here, we asked whether LBP rescues the retinal morphology and function in rd1 mouse, a photoreceptor fast-degenerating animal model of retinitis pigmentosa, and in particular focused on LBP's effects on the function of retinal ganglion cells (RGCs) during photoreceptor degeneration. Methods: An equal volume of LBP or control vehicle was daily intraperitoneal (i.p.) injected in rd1 mice from postnatal day 4 (P4) to P14, P20, or P24 when photoreceptors completely degenerate. Immunostaining, electroretinogram (ERG), visual behavior tests and multielectrode array (MEA) recordings were assessed to determine the structure and function of the treated retina. Results: LBP treatment greatly promoted photoreceptor survival, enhanced ERG responses, and improved visual behaviors in rd1 mice. MEA data showed that LBP treatment in general decreased the abnormally high spontaneous spiking that occurs in rd1 mice, and increased the percentage of light-responsive RGCs as well as their light-evoked response, light sensitivity, signal-to-noise ratio, and response speed. Interestingly, LBP treatment affected ON and OFF responses differently. Conclusions: LBP improves retinal morphology and function in rd1 mice, and delays the functional decay of RGCs during photoreceptor degeneration. This is the first study that has examined in detail the effects of LBP on RGC responses. Our data suggest that LBP may help extend the effective time window before more invasive RP therapeutic approaches such as retinoprosthesis are applied.
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Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Retinose Pigmentar/prevenção & controle , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Eletrorretinografia , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Células Fotorreceptoras de Vertebrados/fisiologia , Retinose Pigmentar/fisiopatologia , Visão Ocular/fisiologiaRESUMO
Light exerts influences on many physiological and behavioural functions in humans. These functions can be described as image-forming (IF) and non-image forming (NIF) visual processes, both originating in the retina of the eye. Image-forming refers to vision; the process of detecting and distinguishing shapes and colour of objects. Non-image forming refers to detecting level of light intensity or brightness of ambient space, which affects basal physiology such as cycles of rest and activity or the endocrine system. Rod and cone photoreceptors in the outer retinal layer are most important for imageforming vision, while non-image forming functions depend upon additional input from the photopigment melanopsin, which is expressed in retinal ganglion cells (RGC) that makes these cells photosensitive (pRGC). Projections of these pRGCs convey light-induced electrical impulses to a number of brain regions. Visual acuity and colour contrast naturally diminishes with age but dementia often has major effects on the visual processing systems, which impact on the quality of life. The ability of humans to manipulate their light exposure has the immediate potential to either create problems with human physiology (as in shift workers) or to compensate physiological disadvantages (of IF and NIF visual impairment). This mini-review describes the impact of aging on the function of the eye with respect to nonimage forming effects of light, summarises light intervention studies for sleep and neuropsychiatric symptoms and considers implications from photoreceptor-weighted light intensities for biologically effective light intervention and lighting solutions for patients with dementia.
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Envelhecimento/fisiologia , Transtornos Mentais/terapia , Células Fotorreceptoras de Vertebrados/fisiologia , Fototerapia , Transtornos do Sono-Vigília/terapia , Idoso , Animais , Humanos , Transtornos Mentais/fisiopatologia , Sono/fisiologia , Transtornos do Sono-Vigília/fisiopatologia , Visão Ocular/fisiologiaRESUMO
Vision impairment in retinal degenerative diseases such as age-related macular degeneration is primarily associated with photoreceptor degeneration, in which oxidative stress and inflammatory responses are mechanistically involved as central players. Therapies with photoreceptor protective properties remain to be developed. Apigenin-7-diglucuronide (A7DG), a flavonoid glycoside, is present in an assortment of medicinal plants with anti-inflammatory or ant-oxidant activities. However, the pharmacological significance of A7DG remains unknown in vivo. The current study isolated A7DG from Glechoma longituba (Nakai) Kuprian and investigated the retinal protective effect A7DG in mice characterized by bright light-induced photoreceptor degeneration. The results showed that A7DG treatment led to remarkable photoreceptor protection in bright light-exposed BALB/c mice. Moreover, A7DG treatment alleviated photoreceptor apoptosis, mitigated oxidative stress, suppressed reactive gliosis and microglial activation and attenuated the expression of proinflammatory genes in bright light-exposed retinas. The results demonstrated for the first time remarkable photoreceptor protective activities of A7DG in vivo. Inhibition of bright light-induced retinal oxidative stress and retinal inflammatory responses was associated with the retinal protection conferred by A7DG. The work here warrants further evaluation of A7DG as a pharmacological candidate for the treatment of vision-threatening retinal degenerative disorders. Moreover, given the general implication of oxidative stress and inflammation in the pathogenesis of neurodegeneration, A7DG could be further tested for the treatment of other neurodegenerative disorders.
Assuntos
Apigenina/uso terapêutico , Retina/efeitos dos fármacos , Animais , Apigenina/metabolismo , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Eletrorretinografia/efeitos dos fármacos , Inflamação/patologia , Luz/efeitos adversos , Degeneração Macular/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/fisiologia , Substâncias Protetoras/farmacologia , Lesões Experimentais por Radiação/patologia , Retina/metabolismo , Degeneração Retiniana/patologiaRESUMO
PURPOSE: To analyse pupil responses to specific chromatic stimuli in patients with advanced retinitis pigmentosa (RP) to ascertain whether chromatic pupillography can be used as an objective marker for residual retinal function. To examine correlations between parameters of the pupil response and the perception threshold of electrically evoked phosphenes. METHODS: Chromatic pupillography was performed in 40 patients with advanced RP (visual acuity < 0.02 or visual field ≤5°, non-recordable ERGs) and 40 age-matched healthy subjects. Pupil responses to full-field red (605 nm) and blue (420 nm) stimuli of 28 lx corneal illumination were recorded and analysed for two stimulus durations (1 and 4 seconds). The perception threshold of phosphenes to transcorneal electrostimulation was ascertained and correlated to the pupil responses and visual acuity. RESULTS: Patients with RP showed significantly reduced pupil responses to red and blue stimuli compared with the controls. With red stimuli, pupillary escape could be observed; blue stimuli resulted in a well-preserved postillumination pupil response. Phosphene thresholds were significantly increased in patients with RP and correlated with the parameters of the pupil response if all subjects were considered. Within the RP group alone, this relationship was less pronounced and statistically not significant. CONCLUSIONS: Chromatic pupillography demonstrated a significant decrease in outer retinal photoreceptor responses but a persisting and disinhibited intrinsic photosensitive retinal ganglion cell function in advanced RP. These phenomena may be useful as an objective marker for the efficacy of any interventional treatment for hereditary retinal diseases as well as for the selection of suitable patients for an electronic retinal implant.
Assuntos
Técnicas de Diagnóstico Oftalmológico , Estimulação Elétrica/métodos , Células Fotorreceptoras de Vertebrados/fisiologia , Reflexo Pupilar/fisiologia , Células Ganglionares da Retina/fisiologia , Retinose Pigmentar/fisiopatologia , Acuidade Visual , Córnea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Reprodutibilidade dos Testes , Retinose Pigmentar/diagnósticoRESUMO
OBJECTIVES: The discovery of the blue lightsensitive retinal photoreceptor responsible for signaling daytime to the brain suggested that light to the circadian system could be inhibited by using blue-blocking orange tinted glasses. Blue-blocking (BB) glasses are a potential treatment option for bipolar mania. We examined the effectiveness of BB glasses in hospitalized patients with bipolar disorder in a manic state. METHODS: In a single-blinded, randomized, placebo-controlled trial (RCT), eligible patients (with bipolar mania; age 18-70 years) were recruited from five clinics in Norway. Patients were assigned to BB glasses or placebo (clear glasses) from 6 p.m. to 8 a.m. for 7 days, in addition to treatment as usual. Symptoms were assessed daily by use of the Young Mania Rating Scale (YMRS). Motor activity was assessed by actigraphy, and compared to data from a healthy control group. Wearing glasses for one evening/night qualified for inclusion in the intention-to-treat analysis. RESULTS: From February 2012 to February 2015, 32 patients were enrolled. Eight patients dropped out and one was excluded, resulting in 12 patients in the BB group and 11 patients in the placebo group. The mean decline in YMRS score was 14.1 [95% confidence interval (CI): 9.7-18.5] in the BB group, and 1.7 (95% CI: -4.0 to 7.4) in the placebo group, yielding an effect size of 1.86 (Cohen's d). In the BB group, one patient reported headache and two patients experienced easily reversible depressive symptoms. CONCLUSIONS: This RCT shows that BB glasses are effective and feasible as add-on treatment for bipolar mania.
Assuntos
Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/terapia , Percepção de Cores/fisiologia , Óculos , Células Fotorreceptoras de Vertebrados/fisiologia , Transdução de Sinais/fisiologia , Adolescente , Adulto , Idoso , Antimaníacos/uso terapêutico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Encéfalo/fisiopatologia , Ritmo Circadiano/fisiologia , Terapia Combinada , Estudos de Viabilidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Psicometria , Método Simples-Cego , Adulto JovemRESUMO
Tomato (Solanum lycopersicum) is rich in anthocyanins, which are polyphenolic pigments. This study aimed to analyze and characterize the anthocyanin composition in cultivated blue tomato in Japan. The extracts of peel, seed, and pulp of tomatoes were purified following which anthocyanins and lycopene contents were analyzed using high-performance liquid chromatography and electrospray ionization mass spectrometry. Eleven types of anthocyanins were identified, including delphinidin, petunidin, and malvidin. Further, the antioxidant activity of anthocyanins was evaluated using 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt radical quenching assays and electron spin resonance. "Blue tomato" extracts exert antioxidant activity. Thus, we showed that petunidin was present in the "blue tomato" peel while lycopene was present in the peel and pulp. Additionally, the blue tomato peel extract was found to significantly inhibit H2O2-induced cell death in vitro. This is the first study on cell protective effects of Japanese blue tomato extract and petunidin in murine photoreceptor cells.
Assuntos
Antocianinas/isolamento & purificação , Antioxidantes/isolamento & purificação , Carotenoides/isolamento & purificação , Frutas/química , Solanum lycopersicum/química , Animais , Antocianinas/farmacologia , Antioxidantes/farmacologia , Benzotiazóis/antagonistas & inibidores , Benzotiazóis/metabolismo , Carotenoides/farmacologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Licopeno , Camundongos , Células Fotorreceptoras de Vertebrados/citologia , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/fisiologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Ácidos Sulfônicos/antagonistas & inibidores , Ácidos Sulfônicos/metabolismoRESUMO
Extraretinal photoreceptors located within the medio-basal hypothalamus regulate the photoperiodic control of seasonal reproduction in birds. An action spectrum for this response describes an opsin photopigment with a λmax of â¼ 492 nm. Beyond this however, the specific identity of the photopigment remains unresolved. Several candidates have emerged including rod-opsin; melanopsin (OPN4); neuropsin (OPN5); and vertebrate ancient (VA) opsin. These contenders are evaluated against key criteria used routinely in photobiology to link orphan photopigments to specific biological responses. To date, only VA opsin can easily satisfy all criteria and we propose that this photopigment represents the prime candidate for encoding daylength and driving seasonal breeding in birds. We also show that VA opsin is co-expressed with both gonadotropin-releasing hormone (GnRH) and arginine-vasotocin (AVT) neurons. These new data suggest that GnRH and AVT neurosecretory pathways are endogenously photosensitive and that our current understanding of how these systems are regulated will require substantial revision.
Assuntos
Proteínas Aviárias/fisiologia , Aves/fisiologia , Hipotálamo/fisiologia , Opsinas/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Estações do Ano , Comportamento Sexual Animal/fisiologia , Animais , Hormônio Liberador de Gonadotropina/biossíntese , Vasotocina/biossínteseRESUMO
OBJECTIVE: Available pharmacological treatment of mania is insufficient. Virtual darkness therapy (blue light-blocking treatment by means of orange-tinted glasses) is a promising new treatment option for mania. The basis for this might be the recently identified blue light-sensitive retinal photoreceptor, which is solely responsible for light stimulus to the circadian master clock. This is the first case report describing the clinical course of a closely monitored, hospitalized patient in a manic episode first receiving clear-lensed, and then blue light-blocking glasses. METHODS: A 58-year-old Caucasian man, with bipolar I disorder and three previous manic episodes, was hospitalized during a manic episode. In addition to pharmacological treatment, he was treated with clear-lensed glasses for seven days, then one day without glasses, followed by six days of blue light-blocking glasses. During the entire observational period, he wore an actigraph with internal light sensors. RESULTS: Manic symptoms were unaltered during the first seven days. The transition to the blue-blocking regime was followed by a rapid and sustained decline in manic symptoms accompanied by a reduction in total sleep, a reduction in motor activity during sleep intervals, and markedly increased regularity of sleep intervals. The patient's total length of hospital stay was 20 days shorter than the average time during his previous manic episodes. CONCLUSIONS: The unusually rapid decline in symptoms, accompanied by uniform sleep parameter changes toward markedly increased regularity, suggest that blue-blockers might be targeting a central mechanism in the pathophysiology of mania that needs to be explored both in clinical research and in basic science.
Assuntos
Transtorno Bipolar/terapia , Cromoterapia , Luz , Privação Sensorial , Sono/efeitos da radiação , Óculos , Humanos , Masculino , Pessoa de Meia-Idade , Células Fotorreceptoras de Vertebrados/fisiologiaRESUMO
Low-level electrical stimulation applied to the eye has been shown to have neuroprotective effects on photoreceptors and retinal ganglion cells. In this review, we compare the effects of Subretinal Electrical Stimulation (SES), Transcorneal Electrical Stimulation (TES), and Whole Eye Stimulation (WES) on preserving retinal structure and function, and visual acuity, in retinal degeneration. Similarities and differences in stimulus parameters, targeted cells and growth factor expression will be discussed with emphasis on studies that have translated laboratory findings into clinical trials.
Assuntos
Terapia por Estimulação Elétrica/métodos , Células Fotorreceptoras de Vertebrados/fisiologia , Degeneração Retiniana/terapia , Células Ganglionares da Retina/fisiologia , Animais , Humanos , Células Fotorreceptoras de Vertebrados/citologia , Células Ganglionares da Retina/citologiaRESUMO
Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.
Assuntos
Adaptação à Escuridão/fisiologia , Modelos Neurológicos , Células Fotorreceptoras de Vertebrados/fisiologia , Tálamo/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Percepção Visual/fisiologia , Animais , Gatos , Escuridão , Potenciais Evocados Visuais/fisiologia , Humanos , Luz , Estimulação LuminosaRESUMO
A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.
Assuntos
Inibidores de Adenilil Ciclases , Agonistas alfa-Adrenérgicos/uso terapêutico , Antagonistas Adrenérgicos alfa/uso terapêutico , Degeneração Macular/congênito , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/biossíntese , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/biossíntese , Receptores Adrenérgicos alfa 2/biossíntese , Antagonistas da Serotonina/uso terapêutico , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/genética , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/uso terapêutico , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Oxirredutases do Álcool/deficiência , Oxirredutases do Álcool/genética , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Doxazossina/farmacologia , Doxazossina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Guanabenzo/farmacologia , Guanabenzo/uso terapêutico , Humanos , Luz/efeitos adversos , Macaca fascicularis , Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Degeneração Macular/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Células Fotorreceptoras de Vertebrados/patologia , Células Fotorreceptoras de Vertebrados/fisiologia , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Espécies Reativas de Oxigênio , Receptor 5-HT2A de Serotonina/genética , Receptores Adrenérgicos alfa 2/genética , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Antagonistas da Serotonina/farmacologia , Transdução de Sinais , Doença de StargardtRESUMO
Müller cells are not only the main glial cell type in the retina but also latent progenitor/stem cells, which in pathological conditions can transdifferentiate to a neuronal phenotype and regenerate the neurons lost in a mature retina. Several signal transduction pathways can induce the dedifferentiation of mature Müller cells to a progenitor-like state, including that stimulated by glutamate. However, the precise molecular mechanisms by which terminally differentiated cells are initially primed to acquire multipotency remain unclear. In the present study, we have characterized early genetic and epigenetic events that occur immediately after glutamate-induced dedifferentiation of fully differentiated Müller cells is initiated. Using Müller cell-enriched cultures from postnatal rats, we demonstrate that glutamate triggers a rapid dedifferentiation response characterized by changes in cell morphology coupled to the induction of progenitor cell marker gene expression (e.g., nestin, lin28 and sox2) within 1h. Dedifferentiation involved the activation of N-methyl-d-aspartate and type II metabotropic glutamate receptors, as well as global DNA demethylation (evident through the decrease in methyl-CpG-binding protein 2 immunoreactivity) and an increase in gadd45-ß gene expression; although, early progenitor gene expression was only partially inhibited by pharmacological impairment of DNA methylation. Importantly, the expression of Müller glia identity genes (i.e., glutamine synthetase; cellular retinaldehyde binding protein, CRALBP) is retained through the process. Dedifferentiated Müller cells held an early neuronal differentiation potential similar to that observed in retinal progenitor-enriched cultures but, contrary to the latter, dedifferentiated Müller cells failed to further differentiate into mature photoreceptor lineages. We speculate that, in spite of the initial triggering of the dedifferentiation pathways, these cells may exhibit a certain degree of epigenetic memory that precludes them from further differentiation.
Assuntos
Desdiferenciação Celular/fisiologia , Células Ependimogliais/fisiologia , Epigênese Genética/fisiologia , Ácido Glutâmico/farmacologia , Fenótipo , Células Fotorreceptoras de Vertebrados/fisiologia , Animais , Desdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Ependimogliais/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Ratos , Ratos Long-Evans , Retina/citologia , Retina/efeitos dos fármacos , Retina/fisiologiaRESUMO
PURPOSE: To define the retinal structural abnormalities in a patient with vitamin A deficiency. METHODS: The patient had a complete ophthalmic examination, electroretinography (ERG), short-wave fundus autofluorescence (SW-AF) and spectral domain optical coherence tomography (SD-OCT) imaging. Serum vitamin A levels were measured. RESULTS: A 63-year-old man with alcoholic cirrhosis, sclerosing cholangitis and chronic pancreatitis experienced blurred vision and nyctalopia for over a year. There was no family history of eye disorders or consanguinity. His best-corrected visual acuity was 20/20 in each eye; color vision as determined with Ishihara color plates was normal in each eye. Anterior segment examination was unremarkable. He was pseudophakic in both eyes. Standard ERGs showed non-detectable rod function, a cone-mediated dark-adapted response to the standard flash and borderline reduced cone function. Serum vitamin A levels were below 0.06 mg/L (normal 0.3-1.2 mg/L). Fundus examination revealed numerous round yellow-white lesions along the superior arcade and nasal to the optic nerve in both eyes. These lesions were hypoautofluorescent on SW-AF. SD-OCT cross sections demonstrated that they were focal disruptions distal to the ellipsoid band of the photoreceptors with hyperreflective images bulging up the ellipsoid and region. The retinal pigment epithelium and the inner retina appeared intact. Limited and gradual vitamin A supplementation for over a month (20 000 IU/day) led to a dramatic improvement in retinal function and to the resolution of the symptoms. The retinal lesions remained unchanged. CONCLUSIONS: Imaging of this patient with nyctalopia and severe rod dysfunction suggests that the retinal white lesions known to occur in vitamin A deficiency localize to the photoreceptor layer, particularly the outer segment. On OCT, they are reminiscent of lesions observed in genetic diseases with retinoid cycle dysfunction and of drusenoid subretinal deposits, an abnormality commonly associated with age-related macular degeneration.
Assuntos
Cegueira Noturna/diagnóstico , Retina/patologia , Deficiência de Vitamina A/diagnóstico , Eletrorretinografia , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Cegueira Noturna/fisiopatologia , Células Fotorreceptoras de Vertebrados/fisiologia , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Vitamina A/sangue , Deficiência de Vitamina A/fisiopatologiaRESUMO
In mammals, photoreception is restricted to cones, rods and a subset of retinal ganglion cells. By contrast, non-mammalian vertebrates possess many extraocular photoreceptors but in many cases the role of these photoreceptors and their underlying photopigments is unknown. In birds, deep brain photoreceptors have been shown to sense photic changes in daylength (photoperiod) and mediate seasonal reproduction. Nonetheless, the specific identity of the opsin photopigment 'sensor' involved has remained elusive. Previously, we showed that vertebrate ancient (VA) opsin is expressed in avian hypothalamic neurons and forms a photosensitive molecule. However, a direct functional link between VA opsin and the regulation of seasonal biology was absent. Here, we report the in vivo and in vitro absorption spectra (λ(max) = ~490 nm) for chicken VA photopigments. Furthermore, the spectral sensitivity of these photopigments match the peak absorbance of the avian photoperiodic response (λ(max) = 492 nm) and permits maximum photon capture within the restricted light environment of the hypothalamus. Such a correspondence argues strongly that VA opsin plays a key role in regulating seasonal reproduction in birds.
Assuntos
Galinhas/fisiologia , Hipotálamo/fisiologia , Opsinas/fisiologia , Estimulação Luminosa , Fotoperíodo , Células Fotorreceptoras de Vertebrados/fisiologia , Animais , Western Blotting , Cromatografia de Afinidade , Células HEK293 , Hemoglobinas/fisiologia , Hemoglobinas/efeitos da radiação , Humanos , Hipotálamo/citologia , Opsinas/efeitos da radiação , Células Fotorreceptoras de Vertebrados/química , Isoformas de Proteínas/fisiologia , Isoformas de Proteínas/efeitos da radiação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/efeitos da radiação , Reprodução , Retinaldeído , Estações do Ano , EspectrofotometriaRESUMO
In the aging human eye, oxidative damage and accumulation of pro-oxidant lysosomal lipofuscin cause functional decline of the retinal pigment epithelium (RPE), which contributes to age-related macular degeneration. In mice with an RPE-specific phagocytosis defect due to lack of αvß5 integrin receptors, RPE accumulation of lipofuscin suggests that the age-related blindness we previously described in this model may also result from oxidative stress. Cellular and molecular targets of oxidative stress in the eye remain poorly understood. Here we identify actin among 4-hydroxynonenal (HNE) adducts formed specifically in ß5(-/-) RPE but not in neural retina with age. HNE modification directly correlated with loss of resistance of actin to detergent extraction, suggesting cytoskeletal damage in aging RPE. Dietary enrichment with natural antioxidants, grapes or marigold extract containing macular pigments lutein/zeaxanthin, was sufficient to prevent HNE-adduct formation, actin solubility, lipofuscin accumulation, and age-related cone and rod photoreceptor dysfunction in ß5(-/-) mice. Acute generation of HNE adducts directly destabilized actin but not tubulin cytoskeletal elements of RPE cells. These findings identify destabilization of the actin cytoskeleton as a consequence of a physiological, sublethal oxidative burden of RPE cells in vivo that is associated with age-related blindness and that can be prevented by consuming an antioxidant-rich diet.